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Pafili K, Zaharia OP, Strassburger K, Knebel B, Herder C, Huttasch M, Karusheva Y, Kabisch S, Strom A, Nowotny B, Szendroedi J, Roden M. PNPLA3 gene variation modulates diet-induced improvement in liver lipid content in type 2 diabetes. Clin Nutr 2025; 48:6-15. [PMID: 40090039 DOI: 10.1016/j.clnu.2025.02.032] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2025] [Accepted: 02/28/2025] [Indexed: 03/18/2025]
Abstract
BACKGROUND&AIMS Lifestyle-induced weight reduction remains crucial for managing type 2 diabetes and steatotic liver disease, but its effectiveness varies. We postulated that the G allele in the rs738409 single nucleotide polymorphism within patatin-like phospholipase domain-containing protein 3 (PNPLA3), which associates with metabolic dysfunction-associated steatotic liver disease, also modulates diet-related metabolic effects. METHODS Participants with type 2 diabetes were randomized to 8-week hypocaloric diets (energy intake: -1,256 kJ/d of, <30 kcal% fat): high in cereal fiber and coffee excluding red meat (HF-RM + C; n = 16), or low in cereal fiber, devoid of coffee, but high in red meat (LF + RM-C; n = 15). Whole-body insulin sensitivity (M value) was assessed using [2H]glucose and hyperinsulinemic-normoglycemic clamps, hepatic lipid content (HCL) and body fat volumes by magnetic resonance spectroscopy/imaging before and after intervention. RESULTS Despite comparable weight loss, HCL decreased more in non-carriers (-65 %) than in G-allele carriers (-36 %) upon HF-RM + C diet (both p < 0.05 vs baseline and between groups), but only among non-carriers (-46 %, p < 0.05 vs baseline) upon LF + RM-C. Upon HF-RM + C diet, increase in insulin sensitivity was not different between carriers (+27 % p = 0.051 from baseline) and non-carriers (+21 %, p = 0.032 from baseline), p > 0.05 for between-group comparison. Upon LF + RM-C diet, both groups equally improved their whole-body insulin sensitivity (+42 % for non-carriers and +37 % for carriers, p < 0.05 vs baseline). Upon HF-RM + C diet, non-carriers decreased circulating interleukin-18 from baseline by -31 %, whereas, upon LF + RM-C diet, non-carriers decreased circulating anti-inflammatory interleukin-1 receptor antagonist levels by 14 % (both p < 0.05 vs baseline). CONCLUSIONS Humans with the PNPLA3 G-allele show modified dietary-induced effects on steatotic liver disease in type 2 diabetes despite body weight reduction. Registration at Clinicaltrials.gov, Identifier number: NCT01409330.
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Affiliation(s)
- Kalliopi Pafili
- Department of Endocrinology and Diabetology, Medical Faculty and University Hospital Düsseldorf, Heinrich-Heine-University Düsseldorf, Moorenstr. 5, 40225 Düsseldorf, Germany; Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich-Heine-University Düsseldorf, Auf'm Hennekamp 65, 40225 Düsseldorf, Germany; German Center for Diabetes Research (DZD), Ingolstädter Landstr. 1, 85764 Neuherberg, Germany
| | - Oana-Patricia Zaharia
- Department of Endocrinology and Diabetology, Medical Faculty and University Hospital Düsseldorf, Heinrich-Heine-University Düsseldorf, Moorenstr. 5, 40225 Düsseldorf, Germany; Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich-Heine-University Düsseldorf, Auf'm Hennekamp 65, 40225 Düsseldorf, Germany; German Center for Diabetes Research (DZD), Ingolstädter Landstr. 1, 85764 Neuherberg, Germany
| | - Klaus Strassburger
- Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich-Heine-University Düsseldorf, Auf'm Hennekamp 65, 40225 Düsseldorf, Germany; Institute for Biometrics and Epidemiology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich-Heine-University Düsseldorf, Auf'm Hennekamp 65, 40225 Düsseldorf, Germany
| | - Birgit Knebel
- German Center for Diabetes Research (DZD), Ingolstädter Landstr. 1, 85764 Neuherberg, Germany; Institute for Clinical Biochemistry and Pathobiochemistry, German Diabetes Center, Leibniz Institute for Diabetes Research at Heinrich-Heine-University, Auf'm Hennekamp 65, 40225 Düsseldorf, Germany
| | - Christian Herder
- Department of Endocrinology and Diabetology, Medical Faculty and University Hospital Düsseldorf, Heinrich-Heine-University Düsseldorf, Moorenstr. 5, 40225 Düsseldorf, Germany; Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich-Heine-University Düsseldorf, Auf'm Hennekamp 65, 40225 Düsseldorf, Germany; German Center for Diabetes Research (DZD), Ingolstädter Landstr. 1, 85764 Neuherberg, Germany
| | - Maximilian Huttasch
- Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich-Heine-University Düsseldorf, Auf'm Hennekamp 65, 40225 Düsseldorf, Germany; German Center for Diabetes Research (DZD), Ingolstädter Landstr. 1, 85764 Neuherberg, Germany
| | - Yanislava Karusheva
- Department of Endocrinology and Diabetology, Medical Faculty and University Hospital Düsseldorf, Heinrich-Heine-University Düsseldorf, Moorenstr. 5, 40225 Düsseldorf, Germany; Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich-Heine-University Düsseldorf, Auf'm Hennekamp 65, 40225 Düsseldorf, Germany
| | - Stefan Kabisch
- German Center for Diabetes Research (DZD), Ingolstädter Landstr. 1, 85764 Neuherberg, Germany; Department of Endocrinology and Metabolic Medicine, Charité Universitätsmedizin Berlin, Campus Benjamin Franklin, Hindenburgdamm 30, 12203 Berlin, Germany
| | - Alexander Strom
- Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich-Heine-University Düsseldorf, Auf'm Hennekamp 65, 40225 Düsseldorf, Germany; German Center for Diabetes Research (DZD), Ingolstädter Landstr. 1, 85764 Neuherberg, Germany
| | - Bettina Nowotny
- Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich-Heine-University Düsseldorf, Auf'm Hennekamp 65, 40225 Düsseldorf, Germany; Bayer AG, Research and Development Pharmaceuticals, Aprather Weg 42113 Wuppertal, Germany
| | - Julia Szendroedi
- German Center for Diabetes Research (DZD), Ingolstädter Landstr. 1, 85764 Neuherberg, Germany; Department for Internal Medicine I, University Hospital Heidelberg, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany
| | - Michael Roden
- Department of Endocrinology and Diabetology, Medical Faculty and University Hospital Düsseldorf, Heinrich-Heine-University Düsseldorf, Moorenstr. 5, 40225 Düsseldorf, Germany; Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich-Heine-University Düsseldorf, Auf'm Hennekamp 65, 40225 Düsseldorf, Germany; German Center for Diabetes Research (DZD), Ingolstädter Landstr. 1, 85764 Neuherberg, Germany.
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Souza M, Al-Sharif L, Diaz I, Mantovani A, Villela-Nogueira CA. Global Epidemiology and Implications of PNPLA3 I148M Variant in Metabolic Dysfunction-Associated Steatotic Liver Disease: A Systematic Review and Meta-analysis. J Clin Exp Hepatol 2025; 15:102495. [PMID: 39882540 PMCID: PMC11773032 DOI: 10.1016/j.jceh.2024.102495] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/03/2024] [Accepted: 12/18/2024] [Indexed: 01/31/2025] Open
Abstract
BACKGROUND & AIMS PNPLA3 rs738409 variant is a risk factor for onset and progression of metabolic dysfunction-associated steatotic liver disease (MASLD). We aimed to assess its global prevalence, clinical and histological characteristics, and long-term outcomes in patients with MASLD. METHODS PubMed and Embase databases were searched until December 30, 2023, for observational studies on PNPLA3 genotyped adults with MASLD. Proportions were pooled using a generalized linear mixed model with Clopper-Pearson intervals. Continuous and dichotomous variables were analyzed using the DerSimonian-Laird method. International Prospective Register of Systematic Reviews registration number: CRD42023449838. RESULTS A total of 109 studies involving 118,302 individuals with MASLD were identified. The overall minor allele frequency of the G allele [MAF(G)] at PNPLA3 was 0.45 (95% confidence interval [CI]: 0.43; 0.48) with high heterogeneity (I2 = 98%). The highest MAF(G) was found in Latin America (0.63) and the lowest in Europe (0.38). No African countries were identified. Carriers of the PNPLA3 variant had reduced adiposity, altered fat metabolism, and worse liver damage/histology than noncarriers. There was significant heterogeneity in the clinical/histological analyses (I2 > 50%). Only the PNPLA3 GG genotype was associated with higher mortality and liver-related events with no heterogeneity (I2 = 0%). Metaregressions showed the influence of adiposity, age, diabetes mellitus, and glucose on some PNPLA3 expression parameters. Overall, there was a moderate risk of bias in the included studies. CONCLUSIONS This study reveals the global pattern of PNPLA3 and its clinical, histological, and outcome implications in MASLD. Patients with MASLD and PNPLA3 variant have different clinical features and worse liver severity, and only PNPLA3 GG has a higher risk of mortality and liver outcomes. Our findings highlight the importance of PNPLA3 genotyping in clinical trials and advocate for personalized medicine approaches.
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Affiliation(s)
- Matheus Souza
- Department of Internal Medicine, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
| | | | - Ivanna Diaz
- Department of Internal Medicine, SUNY Downstate Health Sciences University, Brooklyn, NY, United States
| | - Alessandro Mantovani
- Section of Endocrinology, Diabetes and Metabolism, University and Azienda Ospedaliera Universitaria Integrata of Verona, Verona, Italy
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Kuchay MS, Choudhary NS, Ramos-Molina B. Pathophysiological underpinnings of metabolic dysfunction-associated steatotic liver disease. Am J Physiol Cell Physiol 2025; 328:C1637-C1666. [PMID: 40244183 DOI: 10.1152/ajpcell.00951.2024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2025] [Revised: 01/31/2025] [Accepted: 03/31/2025] [Indexed: 04/18/2025]
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) is emerging as the leading cause of chronic liver disease worldwide, reflecting the global epidemics of obesity, metabolic syndrome, and type 2 diabetes. Beyond its strong association with excess adiposity, MASLD encompasses a heterogeneous population that includes individuals with normal body weight ("lean MASLD") highlighting the complexity of its pathogenesis. This disease results from a complex interplay between genetic susceptibility, epigenetic modifications, and environmental factors, which converge to disrupt metabolic homeostasis. Adipose tissue dysfunction and insulin resistance trigger an overflow of lipids to the liver, leading to mitochondrial dysfunction, oxidative stress, and hepatocellular injury. These processes promote hepatic inflammation and fibrogenesis, driven by cross talk among hepatocytes, immune cells, and hepatic stellate cells, with key contributions from gut-liver axis perturbations. Recent advances have unraveled pivotal molecular pathways, such as transforming growth factor-β signaling, Notch-induced osteopontin, and sphingosine kinase 1-mediated responses, that orchestrate fibrogenic activation. Understanding these interconnected mechanisms is crucial for developing targeted therapies. This review integrates current knowledge on the pathophysiology of MASLD, emphasizing emerging concepts such as lean metabolic dysfunction-associated steatohepatitis (MASH), epigenetic alterations, hepatic extracellular vesicles, and the relevance of extrahepatic signals. It also discusses novel therapeutic strategies under investigation, aiming to provide a comprehensive and structured overview of the evolving MASLD landscape for both basic scientists and clinicians.
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Affiliation(s)
| | - Narendra Singh Choudhary
- Institute of Digestive and Hepatobiliary Sciences, Medanta-The Medicity Hospital, Gurugram, India
| | - Bruno Ramos-Molina
- Group of Obesity, Diabetes & Metabolism, Biomedical Research Institute of Murcia (IMIB), Murcia, Spain
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Park JH, Park KJ. Genetic variants associated with metabolic dysfunction-associated fatty liver diseases in a Korean population. Eur J Med Res 2025; 30:318. [PMID: 40264238 PMCID: PMC12016408 DOI: 10.1186/s40001-025-02576-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2025] [Accepted: 04/09/2025] [Indexed: 04/24/2025] Open
Abstract
BACKGROUND Susceptibility to metabolic dysfunction-associated fatty liver diseases (MAFLD) shows a large inter-ethnic variability. Currently, large-scale genome-wide association studies (GWAS) on MAFLD in a Korean population are limited. This study aimed to investigate genes underlying MAFLD in a Korean population. METHODS A total of 13,457 Korean adults (4061 cases and 9396 controls) who underwent abdominal ultrasonography, biochemical testing, and genetic studies at a comprehensive health promotion center from 2019 to 2023 were included. Genome-wide genotyping was conducted using Infinium Asian Screening Array and an iSCAN system (Illumina, San Diego, CA, USA). Gene-based approach was conducted with Multi-Marker Analysis for Genomic Annotation (MAGMA) and Functional Mapping and Annotation (FUMA). Expression quantitative trait loci (eQTLs) mapping was done using GTEx v8 data. RESULTS The 22q13.3, 19p13.11, and 2p23.3 loci were associated with MAFLD after adjusting for age, sex, and body mass index (p < 5 × 10-8). Of these, 154 (89%) variants were identified as eQTLs (FDR < 0.05). Gene-based approach showed that PNPLA3, SAMM50, and PARVB were significantly associated with MAFLD (Bonferroni-corrected p < 2.99 × 10-6), followed by PDLIM4, GCKR, APOB, GPAM, HMGA1, C5orf56, and APOC1. CONCLUSIONS This is the largest-scale GWAS of MAFLD in a Korean adult population. Genotyping PARVB as well as PNPLA3 might help us identify individuals with the highest risk of MAFLD in Korean adults. These findings would contribute to our understanding of genetic pathogenesis of MAFLD in the Korean population.
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Affiliation(s)
- Jong-Ho Park
- Precision Medicine Center, Seoul National University Bundang Hospital, Seongnam, South Korea
- Department of Genomic Medicine, Seoul National University Bundang Hospital, Seongnam, South Korea
| | - Kyoung-Jin Park
- Department of Laboratory Medicine & Genetics, Samsung Changwon Hospital, Sungkyunkwan University School of Medicine, Changwon, South Korea.
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Eslam M, Fan JG, Yu ML, Wong VWS, Cua IH, Liu CJ, Tanwandee T, Gani R, Seto WK, Alam S, Young DY, Hamid S, Zheng MH, Kawaguchi T, Chan WK, Payawal D, Tan SS, Goh GBB, Strasser SI, Viet HD, Kao JH, Kim W, Kim SU, Keating SE, Yilmaz Y, Kamani L, Wang CC, Fouad Y, Abbas Z, Treeprasertsuk S, Thanapirom K, Al Mahtab M, Lkhagvaa U, Baatarkhuu O, Choudhury AK, Stedman CAM, Chowdhury A, Dokmeci AK, Wang FS, Lin HC, Huang JF, Howell J, Jia J, Alboraie M, Roberts SK, Yoneda M, Ghazinian H, Mirijanyan A, Nan Y, Lesmana CRA, Adams LA, Shiha G, Kumar M, Örmeci N, Wei L, Lau G, Omata M, Sarin SK, George J. The Asian Pacific association for the study of the liver clinical practice guidelines for the diagnosis and management of metabolic dysfunction-associated fatty liver disease. Hepatol Int 2025; 19:261-301. [PMID: 40016576 DOI: 10.1007/s12072-024-10774-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/06/2024] [Accepted: 12/28/2024] [Indexed: 03/01/2025]
Abstract
Metabolic dysfunction-associated fatty liver disease (MAFLD) affects over one-fourth of the global adult population and is the leading cause of liver disease worldwide. To address this, the Asian Pacific Association for the Study of the Liver (APASL) has created clinical practice guidelines focused on MAFLD. The guidelines cover various aspects of the disease, such as its epidemiology, diagnosis, screening, assessment, and treatment. The guidelines aim to advance clinical practice, knowledge, and research on MAFLD, particularly in special groups. The guidelines are designed to advance clinical practice, to provide evidence-based recommendations to assist healthcare stakeholders in decision-making and to improve patient care and disease awareness. The guidelines take into account the burden of clinical management for the healthcare sector.
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Affiliation(s)
- Mohammed Eslam
- Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital and University of Sydney, Westmead, NSW, 2145, Australia.
| | - Jian-Gao Fan
- Center for Fatty Liver, Department of Gastroenterology, Shanghai Key Lab of Pediatric Gastroenterology and Nutrition, Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Ming-Lung Yu
- Hepatobiliary Division, Department of Internal MedicineCollege of Medicine and Center for Liquid Biopsy and Cohort ResearchFaculty of Internal Medicine and Hepatitis Research Center, School of Medicine, College of MedicineSchool of Medicine and Doctoral Program of Clinical and Experimental Medicine, College of Medicine and Center of Excellence for Metabolic Associated Fatty Liver Disease, Kaohsiung Medical University, National Sun Yat-Sen University, Kaohsiung, Taiwan
| | - Vincent Wai-Sun Wong
- Medical Data Analytics Centre, Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Institute of Digestive Disease, Chinese University of Hong Kong, Hong Kong, China
| | - Ian Homer Cua
- Institute of Digestive and Liver Diseases, St. Luke's Medical Center, Global City, Philippines
| | - Chun-Jen Liu
- Division of Gastroenterology and Hepatology, Department of Internal MedicineHepatitis Research CenterGraduate Institute of Clinical Medicine, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Tawesak Tanwandee
- Department of Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Rino Gani
- Department of Internal Medicine, Hepatobiliary Division, Dr. Cipto Mangunkusumo National General Hospital, Universitas Indonesia, Pangeran Diponegoro Road No. 71St, Central Jakarta, 10430, Indonesia
| | - Wai-Kay Seto
- Department of Medicine, School of Clinical Medicine, State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong, China
- Department of Medicine, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China
| | - Shahinul Alam
- Department of Hepatology, Bangabandhu Sheikh Mujib Medical University, Shahbag, Dhaka, Bangladesh
| | - Dan Yock Young
- Department of Medicine, Yong Loo Lin School of Medicine, National University Singapore, Singapore, Singapore
| | - Saeed Hamid
- Department of Medicine, Aga Khan University, Karachi, Pakistan
| | - Ming-Hua Zheng
- MAFLD Research Center, Department of Hepatology, The First Affiliated Hospital of Wenzhou Medical University, Key Laboratory of Diagnosis and Treatment for The Development of Chronic Liver Disease in Zhejiang Province, Wenzhou, China
| | - Takumi Kawaguchi
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan
| | - Wah-Kheong Chan
- Gastroenterology and Hepatology Unit, Department of Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
| | - Diana Payawal
- Department of Medicine, Cardinal Santos Medical Center, Mandaluyong, Philippines
| | - Soek-Siam Tan
- Department of Hepatology, Selayang Hospital, Batu Caves, Malaysia
| | - George Boon-Bee Goh
- Department of Gastroenterology and Hepatology, Singapore General Hospital, Singapore, Singapore
- Medicine Academic Clinical Program, Duke-NUS Medical School, Singapore, Singapore
| | - Simone I Strasser
- AW Morrow Gastroenterology and Liver Centre, Royal Prince Alfred Hospital, Sydney, NSW, Australia
| | - Hang Dao Viet
- Internal Medicine Faculty, Hanoi Medical University, Hanoi, Vietnam
| | - Jia-Horng Kao
- Graduate Institute of Clinical MedicineDepartment of Internal MedicineHepatitis Research CenterDepartment of Medical Research, National Taiwan University College of Medicine, National Taiwan University, National Taiwan University Hospital, 1 Chang-Te Street, 10002, Taipei, Taiwan
| | - Won Kim
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Seoul National University College of Medicine, Seoul Metropolitan Government Boramae Medical Center, Seoul, Republic of Korea
| | - Seung Up Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Severance Hospital, 50-1, Yonsei-Ro, Seodaemun-Gu, Seoul, 03722, Republic of Korea
| | - Shelley E Keating
- School of Human Movement and Nutrition Sciences, The University of Queensland, Brisbane, QLD, 4072, Australia
| | - Yusuf Yilmaz
- Department of Gastroenterology, School of Medicine, Recep Tayyip Erdoğan University, Rize, Turkey
| | | | - Chia-Chi Wang
- Buddhist Tzu Chi Medical Foundation and School of Medicine, Taipei Tzu Chi Hospital, Tzu Chi University, Taipei, Taiwan
| | - Yasser Fouad
- Department of Gastroenterology, Hepatology and Endemic Medicine, Faculty of Medicine, Minia University, Cairo, Egypt
| | - Zaigham Abbas
- Department of Hepatogastroenterology, Dr.Ziauddin University Hospital, Clifton, Karachi, Pakistan
| | | | | | - Mamun Al Mahtab
- Department of Hepatology, Bangabandhu Sheikh Mujib Medical University, Dhaka, Bangladesh
| | - Undram Lkhagvaa
- Department of Health Policy, School of Public Health, Mongolian National University of Medical Sciences, Ulaanbaatar, Mongolia
| | - Oidov Baatarkhuu
- Department of Infectious Diseases, School of Medicine, Mongolian National University of Medical Sciences, Ulaanbaatar, Mongolia
| | - Ashok Kumar Choudhury
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, 110070, India
| | | | - Abhijit Chowdhury
- Department of Hepatology, School of Digestive and Liver Diseases, Institute of Post Graduate Medical Education and Research, Kolkata, India
| | - A Kadir Dokmeci
- Department of Medicine, Ankara University School of Medicine, Ankara, Turkey
| | - Fu-Sheng Wang
- Senior Department of Infectious Diseases, The Fifth Medical Center of Chinese PLA General Hospital, National Clinical Research Center for Infectious Diseases, Chinese PLA Medical School, Chinese PLA General Hospital, Beijing, 100039, China
| | - Han-Chieh Lin
- Division of Gastroenterology and Hepatology, Department of Medicine, Institute of Clinical Medicine, School of Medicine, Taipei Veterans General Hospital, National Yang-Ming Chiao Tung University, No. 201, Section 2, Shipai RdNo. 155, Section 2, Linong St, Beitou District, Taipei City, 112, Taiwan
| | - Jee-Fu Huang
- Hepatobiliary Division, Department of Internal MedicineCollege of Medicine and Center for Liquid Biopsy and Cohort ResearchFaculty of Internal Medicine and Hepatitis Research Center, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Jess Howell
- Burnet Institute, Melbourne, VIC, 3004, Australia
- Department of Epidemiology and Preventive Medicine, Monash University, Clayton, VIC, 3008, Australia
- Department of Medicine, The University of Melbourne, Parkville, VIC, 3050, Australia
- Department of Gastroenterology, St Vincent's Hospital Melbourne, Melbourne, VIC, 3165, Australia
| | - Jidong Jia
- Liver Research Center, Beijing Key Laboratory of Translational Medicine On Liver Cirrhosis, Beijing Friendship Hospital, Capital Medical University, National Clinical Research Center of Digestive Diseases, Beijing, China
| | - Mohamed Alboraie
- Department of Internal Medicine, Al-Azhar University, Cairo, 11884, Egypt
| | - Stuart K Roberts
- Department of Gastroenterology and Hepatology, Central Clinical School, The Alfred, Monash University, Melbourne, Australia
| | - Masato Yoneda
- Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, Yokohama, 236-0004, Japan
| | - Hasmik Ghazinian
- Gastroenterology and Hepatology Department, Yerevan Medical Scientific Center, Yerevan, Armenia
| | - Aram Mirijanyan
- Gastroenterology and Hepatology Department, Yerevan Medical Scientific Center, Yerevan, Armenia
| | - Yuemin Nan
- Department of Traditional and Western Medical Hepatology, Third Hospital of Hebei Medical University, Shijiazhuang, China
| | | | - Leon A Adams
- Medical School, Faculty of Medicine and Health Sciences, The University of Western Australia, Nedlands, WA, Australia
| | - Gamal Shiha
- Hepatology and Gastroenterology Unit, Internal Medicine Department, Faculty of Medicine, Mansoura University, Egyptian Liver Research Institute and Hospital (ELRIAH), Sherbin, El Mansoura, Egypt
| | - Manoj Kumar
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Necati Örmeci
- Department of Gastroenterohepatology, Istanbul Health and Technology University, Istanbul, Turkey
| | - Lai Wei
- Hepatopancreatobiliary Center, Beijing Tsinghua Changgung Hospital, Tsinghua University, Beijing, China
| | - George Lau
- Humanity and Health Medical Group, Humanity and Health Clinical Trial Center, Hong Kong SAR, China
- The Fifth Medical Center of Chinese, PLA General Hospital, Beijing, 100039, China
| | - Masao Omata
- Department of Gastroenterology, Yamanashi Central Hospital, Yamanashi, Japan
- University of Tokyo, Tokyo, Japan
| | - Shiv K Sarin
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India.
| | - Jacob George
- Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital and University of Sydney, Westmead, NSW, 2145, Australia
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Chen VL, Kuppa A, Oliveri A, Chen Y, Ponnandy P, Patel PB, Palmer ND, Speliotes EK. Human genetics of metabolic dysfunction-associated steatotic liver disease: from variants to cause to precision treatment. J Clin Invest 2025; 135:e186424. [PMID: 40166930 PMCID: PMC11957700 DOI: 10.1172/jci186424] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/02/2025] Open
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) is characterized by increased hepatic steatosis with cardiometabolic disease and is a leading cause of advanced liver disease. We review here the genetic basis of MASLD. The genetic variants most consistently associated with hepatic steatosis implicate genes involved in lipoprotein input or output, glucose metabolism, adiposity/fat distribution, insulin resistance, or mitochondrial/ER biology. The distinct mechanisms by which these variants promote hepatic steatosis result in distinct effects on cardiometabolic disease that may be best suited to precision medicine. Recent work on gene-environment interactions has shown that genetic risk is not fixed and may be exacerbated or attenuated by modifiable (diet, exercise, alcohol intake) and nonmodifiable environmental risk factors. Some steatosis-associated variants, notably those in patatin-like phospholipase domain-containing 3 (PNPLA3) and transmembrane 6 superfamily member 2 (TM6SF2), are associated with risk of developing adverse liver-related outcomes and provide information beyond clinical risk stratification tools, especially in individuals at intermediate to high risk for disease. Future work to better characterize disease heterogeneity by combining genetics with clinical risk factors to holistically predict risk and develop therapies based on genetic risk is required.
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Affiliation(s)
- Vincent L. Chen
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA
| | - Annapurna Kuppa
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA
| | - Antonino Oliveri
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA
| | - Yanhua Chen
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA
| | - Prabhu Ponnandy
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA
| | - Puja B. Patel
- Department of Biochemistry, Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA
| | - Nicholette D. Palmer
- Department of Biochemistry, Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA
| | - Elizabeth K. Speliotes
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA
- Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan, USA
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Huang HYR, Vitali C, Zhang D, Hand NJ, Phillips MC, Creasy KT, Scorletti E, Park J, Regeneron Centre, Schneider KM, Rader DJ, Schneider CV. Deep metabolic phenotyping of humans with protein-altering variants in TM6SF2 using a genome-first approach. JHEP Rep 2025; 7:101243. [PMID: 39687601 PMCID: PMC11647476 DOI: 10.1016/j.jhepr.2024.101243] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/09/2024] [Revised: 09/28/2024] [Accepted: 10/07/2024] [Indexed: 12/18/2024] Open
Abstract
Background & Aim An unbiased genome-first approach can expand the molecular understanding of specific genes in disease-agnostic biobanks for deeper phenotyping. TM6SF2 represents a good candidate for this approach due to its known association with steatotic liver disease (SLD). Methods We screened participants with whole-exome sequences in the Penn Medicine Biobank (PMBB, n >40,000) and the UK Biobank (UKB, n >200,000) for protein-altering variants in TM6SF2 and evaluated their association with liver phenotypes and clinical outcomes. Results Missense variants in TM6SF2 (E167K, L156P, P216L) were associated with an increased risk of clinically diagnosed and imaging-proven steatosis, independent of the PNPLA3 I48M risk allele and hepatitis B/C (p <0.001). E167K homozygotes had significantly increased risk of SLD (odds ratio [OR] 5.38, p <0.001), steatohepatitis (OR 5.76, p <0.05) and hepatocellular carcinoma (OR 11.22, p <0.0001), while heterozygous carriers of L156P and P216L were also at an increased risk of steatohepatitis. In addition, carriers of E167K are at a 3-fold increased risk of at-risk MASH (OR 2.75, p <0.001). CT-derived liver fat scores were higher in E167K and L156P in an allele-dose manner (p <0.05). This corresponded with the UKB nuclear magnetic resonance-derived lipidomic analyses (n = 105,348), revealing all carriers to exhibit lower total cholesterol, triglycerides and total choline. In silico predictions suggested that these missense variants cause structural disruptions in the EXPERA domain, leading to reduced protein function. This hypothesis was supported by the association of rare loss-of-function variants in TM6SF2 with an increased risk of SLD (OR 4.9, p <0.05), primarily driven by a novel rare stop-gain variant (W35X) with the same directionality. Conclusion The functional genetic study of protein-altering variants provides insights on the association between loss of TM6SF2 function and SLD and provides the basis for future mechanistic studies. Impact and implications The genome-first approach expands insights into genetic risk factors for steatotic liver disease with TM6SF2 being a focal point due to its known association with plasma lipid traits. Our findings validated the association of two missense variants (E167K and L156P) with increased risk of hepatic steatosis on CT and MRI scans, as well as the risk of clinically diagnosed hepatocellular carcinoma independent of the common PNPLA3 I48M risk variant. Notably, we also identified a predicted deleterious missense variant (P216L) linked to steatotic risk and demonstrated that an aggregated gene burden of rare putative loss-of-function variants was associated with the risk of hepatic steatosis. Combined, this study sets the stage for future mechanistic investigations into the functional consequences of TM6SF2 variants in metabolic dysfunction-associated steatotic liver disease.
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Affiliation(s)
- Helen Ye Rim Huang
- Department of Medicine, Division of Translational Medicine and Human Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Cecilia Vitali
- Department of Medicine, Division of Translational Medicine and Human Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
- Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - David Zhang
- Department of Medicine, Division of Translational Medicine and Human Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Nicholas J. Hand
- Department of Medicine, Division of Translational Medicine and Human Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
- Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Michael C. Phillips
- Department of Medicine, Division of Translational Medicine and Human Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Kate Townsend Creasy
- Department of Biobehavioral Health Sciences, School of Nursing, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Eleonora Scorletti
- Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
- The Institute for Translational Medicine and Therapeutics, The Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Joseph Park
- Department of Medicine, Division of Translational Medicine and Human Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
- NewYork-Presbyterian, Weill Cornell Medical Center, New York, NY 10065, USA
| | | | - Kai Markus Schneider
- Department of Medicine III, Gastroenterology, Metabolic diseases and Intensive Care, University Hospital RWTH Aachen, 52074 Aachen, Germany
- Medical Department 1, Technische Universität, Dresden, Germany
| | - Daniel J. Rader
- Department of Medicine, Division of Translational Medicine and Human Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
- Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
- The Institute for Translational Medicine and Therapeutics, The Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Carolin Victoria Schneider
- The Institute for Translational Medicine and Therapeutics, The Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
- Department of Medicine III, Gastroenterology, Metabolic diseases and Intensive Care, University Hospital RWTH Aachen, 52074 Aachen, Germany
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Sato S, Iino C, Sasada T, Furusawa K, Yoshida K, Sawada K, Mikami T, Fukuda S, Nakaji S, Sakuraba H. A 4-year cohort study of the effects of PNPLA3 rs738409 genotypes on liver fat and fibrosis and gut microbiota in a non-fatty liver population. Environ Health Prev Med 2025; 30:17. [PMID: 40074353 PMCID: PMC11925709 DOI: 10.1265/ehpm.24-00365] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2024] [Accepted: 02/07/2025] [Indexed: 03/14/2025] Open
Abstract
BACKGROUND Many factors are associated with the development and progression of liver fat and fibrosis; however, genetics and the gut microbiota are representative factors. Moreover, recent studies have indicated a link between host genes and the gut microbiota. This study investigated the effect of patatin-like phospholipase domain-containing 3 (PNPLA3) rs738409 (C > G), which has been reported to be most involved in the onset and progression of fatty liver, on liver fat and fibrosis in a cohort study related to gut microbiota in a non-fatty liver population. METHODS This cohort study included 214 participants from the health check-up project in 2018 and 2022 who had non-fatty liver with controlled attenuation parameter (CAP) values <248 dB/m by FibroScan and were non-drinkers. Changes in CAP values and liver stiffness measurement (LSM), liver-related items, and gut microbiota from 2018 to 2022 were investigated separately for PNPLA3 rs738409 CC, CG, and GG genotypes. RESULTS Baseline values showed no difference among the PNPLA3 rs738409 genotypes for any of the measurement items. From 2018 to 2022, the PNPLA3 rs738409 CG and GG genotype groups showed a significant increase in CAP and body mass index; no significant change was observed in the CC genotype group. LSM increased in all genotypes, but the rate of increase was highest in the GG genotype, followed by the CG and CC genotypes. Fasting blood glucose levels increased in all genotypes; however, HOMA-IR (Homeostasis Model Assessment of Insulin Resistance) increased significantly only in the GG genotype. HDL (high-density lipoprotein) and LDL (low-density lipoprotein) cholesterol levels significantly increased in all genotypes, whereas triglycerides did not show any significant changes in any genotype. As for the gut microbiota, the relative abundance of Feacalibacterium in the PNPLA3 rs738409 GG genotype decreased by 2% over 4 years, more than 2-fold compared to CC and GG genotypes. Blautia increased significantly in the CC group. CONCLUSION The results suggest that PNPLA3 G-allele carriers of non-fatty liver develop liver fat and fibrosis due to not only obesity and insulin resistance but also the deterioration of gut microbiota, which may require a relatively long course of time, even years.
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Affiliation(s)
- Satoshi Sato
- Department of Gastroenterology, Hematology and Clinical Immunology, Hirosaki University Graduate School of Medicine, Hirosaki 036-8562, Japan
| | - Chikara Iino
- Department of Gastroenterology, Hematology and Clinical Immunology, Hirosaki University Graduate School of Medicine, Hirosaki 036-8562, Japan
| | - Takafumi Sasada
- Department of Gastroenterology, Hematology and Clinical Immunology, Hirosaki University Graduate School of Medicine, Hirosaki 036-8562, Japan
| | - Keisuke Furusawa
- Department of Gastroenterology, Hematology and Clinical Immunology, Hirosaki University Graduate School of Medicine, Hirosaki 036-8562, Japan
| | - Kenta Yoshida
- Department of Gastroenterology, Hematology and Clinical Immunology, Hirosaki University Graduate School of Medicine, Hirosaki 036-8562, Japan
| | - Kaori Sawada
- Department of Preemptive Medicine, Hirosaki University Graduate School of Medicine, Hirosaki 036-8562, Japan
| | - Tatsuya Mikami
- Department of Preemptive Medicine, Hirosaki University Graduate School of Medicine, Hirosaki 036-8562, Japan
| | - Shinsaku Fukuda
- Department of Preemptive Medicine, Hirosaki University Graduate School of Medicine, Hirosaki 036-8562, Japan
| | - Shigeyuki Nakaji
- Department of Preemptive Medicine, Hirosaki University Graduate School of Medicine, Hirosaki 036-8562, Japan
| | - Hirotake Sakuraba
- Department of Gastroenterology, Hematology and Clinical Immunology, Hirosaki University Graduate School of Medicine, Hirosaki 036-8562, Japan
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Magdy A, Kim HJ, Go H, Lee JM, Sohn HA, Haam K, Jung HJ, Park JL, Yoo T, Kwon ES, Lee DH, Choi M, Kang KW, Kim W, Kim M. DNA methylome analysis reveals epigenetic alteration of complement genes in advanced metabolic dysfunction-associated steatotic liver disease. Clin Mol Hepatol 2024; 30:824-844. [PMID: 39048522 PMCID: PMC11540403 DOI: 10.3350/cmh.2024.0229] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/09/2024] [Revised: 07/22/2024] [Accepted: 07/24/2024] [Indexed: 07/27/2024] Open
Abstract
BACKGROUND/AIMS Blocking the complement system is a promising strategy to impede the progression of metabolic dysfunction-associated steatotic liver disease (MASLD). However, the interplay between complement and MASLD remains to be elucidated. This comprehensive approach aimed to investigate the potential association between complement dysregulation and the histological severity of MASLD. METHODS Liver biopsy specimens were procured from a cohort comprising 106 Korean individuals, which included 31 controls, 17 with isolated steatosis, and 58 with metabolic dysfunction-associated steatohepatitis (MASH). Utilizing the Infinium Methylation EPIC array, thorough analysis of methylation alterations in 61 complement genes was conducted. The expression and methylation of nine complement genes in a murine MASH model were examined using quantitative RT-PCR and pyrosequencing. RESULTS Methylome and transcriptome analyses of liver biopsies revealed significant (P<0.05) hypermethylation and downregulation of C1R, C1S, C3, C6, C4BPA, and SERPING1, as well as hypomethylation (P<0.0005) and upregulation (P<0.05) of C5AR1, C7, and CD59, in association with the histological severity of MASLD. Furthermore, DNA methylation and the relative expression of nine complement genes in a MASH diet mouse model aligned with human data. CONCLUSION Our research provides compelling evidence that epigenetic alterations in complement genes correlate with MASLD severity, offering valuable insights into the mechanisms driving MASLD progression, and suggests that inhibiting the function of certain complement proteins may be a promising strategy for managing MASLD.
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Affiliation(s)
- Amal Magdy
- Aging Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Korea
- Department of Functional Genomics, KRIBB School of Bioscience, Korea University of Science and Technology (UST), Daejeon, Korea
| | - Hee-Jin Kim
- Aging Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Korea
| | - Hanyong Go
- Aging Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Korea
- Department of Functional Genomics, KRIBB School of Bioscience, Korea University of Science and Technology (UST), Daejeon, Korea
| | - Jun Min Lee
- Aging Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Korea
- Department of Functional Genomics, KRIBB School of Bioscience, Korea University of Science and Technology (UST), Daejeon, Korea
| | - Hyun Ahm Sohn
- Aging Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Korea
| | - Keeok Haam
- Aging Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Korea
| | - Hyo-Jung Jung
- Aging Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Korea
| | - Jong-Lyul Park
- Aging Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Korea
- Department of Functional Genomics, KRIBB School of Bioscience, Korea University of Science and Technology (UST), Daejeon, Korea
| | - Taekyeong Yoo
- Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Korea
| | - Eun-Soo Kwon
- Aging Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Korea
- Department of Biomolecular Science, KRIBB School of Bioscience, UST, Daejeon, Korea
| | - Dong Hyeon Lee
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul Metropolitan Government Boramae Medical Center, Seoul, Korea
| | - Murim Choi
- Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Korea
| | - Keon Wook Kang
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Korea
| | - Won Kim
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul Metropolitan Government Boramae Medical Center, Seoul, Korea
| | - Mirang Kim
- Aging Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Korea
- Department of Functional Genomics, KRIBB School of Bioscience, Korea University of Science and Technology (UST), Daejeon, Korea
| | - on behalf of the Innovative Target Exploration of NAFLD (ITEN) Consortium
- Aging Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Korea
- Department of Functional Genomics, KRIBB School of Bioscience, Korea University of Science and Technology (UST), Daejeon, Korea
- Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Korea
- Department of Biomolecular Science, KRIBB School of Bioscience, UST, Daejeon, Korea
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul Metropolitan Government Boramae Medical Center, Seoul, Korea
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Korea
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Abdelhameed F, Kite C, Lagojda L, Dallaway A, Chatha KK, Chaggar SS, Dalamaga M, Kassi E, Kyrou I, Randeva HS. Non-invasive Scores and Serum Biomarkers for Fatty Liver in the Era of Metabolic Dysfunction-associated Steatotic Liver Disease (MASLD): A Comprehensive Review From NAFLD to MAFLD and MASLD. Curr Obes Rep 2024; 13:510-531. [PMID: 38809396 PMCID: PMC11306269 DOI: 10.1007/s13679-024-00574-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 05/14/2024] [Indexed: 05/30/2024]
Abstract
PURPOSE OF REVIEW The prevalence of non-alcoholic fatty liver disease (NAFLD) is rapidly increasing worldwide, making it the leading cause of liver related morbidity and mortality. Currently, liver biopsy is the gold standard for assessing individuals with steatohepatitis and fibrosis. However, its invasiveness, sampling variability, and impracticality for large-scale screening has driven the search for non-invasive methods for early diagnosis and staging. In this review, we comprehensively summarise the evidence on the diagnostic performance and limitations of existing non-invasive serum biomarkers and scores in the diagnosis and evaluation of steatosis, steatohepatitis, and fibrosis. RECENT FINDINGS Several non-invasive serum biomarkers and scores have been developed over the last decade, although none has successfully been able to replace liver biopsy. The introduction of new NAFLD terminology, namely metabolic dysfunction-associated fatty liver disease (MAFLD) and more recently metabolic dysfunction-associated steatotic liver disease (MASLD), has initiated a debate on the interchangeability of these terminologies. Indeed, there is a need for more research on the variability of the performance of non-invasive serum biomarkers and scores across the diagnostic entities of NAFLD, MAFLD and MASLD. There remains a significant need for finding valid and reliable non-invasive methods for early diagnosis and assessment of steatohepatitis and fibrosis to facilitate prompt risk stratification and management to prevent disease progression and complications. Further exploration of the landscape of MASLD under the newly defined disease subtypes is warranted, with the need for more robust evidence to support the use of commonly used serum scores against the new MASLD criteria and validation of previously developed scores.
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Affiliation(s)
- Farah Abdelhameed
- Warwickshire Institute for the Study of Diabetes, Endocrinology and Metabolism (WISDEM), University Hospitals Coventry and Warwickshire NHS Trust, Coventry, CV2 2DX, UK
- Institute for Cardiometabolic Medicine, University Hospitals Coventry and Warwickshire NHS Trust, Coventry, CV2 2DX, UK
| | - Chris Kite
- Warwickshire Institute for the Study of Diabetes, Endocrinology and Metabolism (WISDEM), University Hospitals Coventry and Warwickshire NHS Trust, Coventry, CV2 2DX, UK
- School of Health and Society, Faculty of Education, Health and Wellbeing, University of Wolverhampton, Wolverhampton, WV1 1LY, UK
- Centre for Sport, Exercise and Life Sciences, Research Institute for Health & Wellbeing, Coventry University, Coventry, CV1 5FB, UK
- Chester Medical School, University of Chester, Shrewsbury, SY3 8HQ, UK
| | - Lukasz Lagojda
- Warwickshire Institute for the Study of Diabetes, Endocrinology and Metabolism (WISDEM), University Hospitals Coventry and Warwickshire NHS Trust, Coventry, CV2 2DX, UK
- Clinical Evidence-Based Information Service (CEBIS), University Hospitals Coventry and Warwickshire NHS Trust, Coventry, CV2 2DX, UK
| | - Alexander Dallaway
- Warwickshire Institute for the Study of Diabetes, Endocrinology and Metabolism (WISDEM), University Hospitals Coventry and Warwickshire NHS Trust, Coventry, CV2 2DX, UK
- School of Health and Society, Faculty of Education, Health and Wellbeing, University of Wolverhampton, Wolverhampton, WV1 1LY, UK
| | - Kamaljit Kaur Chatha
- Department of Biochemistry and Immunology, University Hospitals Coventry and Warwickshire NHS Trust, Coventry, CV2 2DX, UK
- Institute for Cardiometabolic Medicine, University Hospitals Coventry and Warwickshire NHS Trust, Coventry, CV2 2DX, UK
| | | | - Maria Dalamaga
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Eva Kassi
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, Athens, Greece
- First Department of Propaupedic and Internal Medicine, Endocrine Unit, Laiko Hospital, National and Kapodistrian University of Athens, 11527, Athens, Greece
| | - Ioannis Kyrou
- Warwickshire Institute for the Study of Diabetes, Endocrinology and Metabolism (WISDEM), University Hospitals Coventry and Warwickshire NHS Trust, Coventry, CV2 2DX, UK.
- Warwick Medical School, University of Warwick, Coventry, CV4 7AL, UK.
- Centre for Sport, Exercise and Life Sciences, Research Institute for Health & Wellbeing, Coventry University, Coventry, CV1 5FB, UK.
- Institute for Cardiometabolic Medicine, University Hospitals Coventry and Warwickshire NHS Trust, Coventry, CV2 2DX, UK.
- Aston Medical School, College of Health and Life Sciences, Aston University, Birmingham, B4 7ET, UK.
- College of Health, Psychology and Social Care, University of Derby, Derby, DE22 1GB, UK.
- Laboratory of Dietetics and Quality of Life, Department of Food Science and Human Nutrition, School of Food and Nutritional Sciences, Agricultural University of Athens, 11855, Athens, Greece.
| | - Harpal S Randeva
- Warwickshire Institute for the Study of Diabetes, Endocrinology and Metabolism (WISDEM), University Hospitals Coventry and Warwickshire NHS Trust, Coventry, CV2 2DX, UK.
- Warwick Medical School, University of Warwick, Coventry, CV4 7AL, UK.
- Centre for Sport, Exercise and Life Sciences, Research Institute for Health & Wellbeing, Coventry University, Coventry, CV1 5FB, UK.
- Institute for Cardiometabolic Medicine, University Hospitals Coventry and Warwickshire NHS Trust, Coventry, CV2 2DX, UK.
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Habib S. Team players in the pathogenesis of metabolic dysfunctions-associated steatotic liver disease: The basis of development of pharmacotherapy. World J Gastrointest Pathophysiol 2024; 15:93606. [PMID: 39220834 PMCID: PMC11362842 DOI: 10.4291/wjgp.v15.i4.93606] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2024] [Revised: 05/14/2024] [Accepted: 07/23/2024] [Indexed: 08/22/2024] Open
Abstract
Nutrient metabolism is regulated by several factors. Social determinants of health with or without genetics are the primary regulator of metabolism, and an unhealthy lifestyle affects all modulators and mediators, leading to the adaptation and finally to the exhaustion of cellular functions. Hepatic steatosis is defined by presence of fat in more than 5% of hepatocytes. In hepatocytes, fat is stored as triglycerides in lipid droplet. Hepatic steatosis results from a combination of multiple intracellular processes. In a healthy individual nutrient metabolism is regulated at several steps. It ranges from the selection of nutrients in a grocery store to the last step of consumption of ATP as an energy or as a building block of a cell as structural component. Several hormones, peptides, and genes have been described that participate in nutrient metabolism. Several enzymes participate in each nutrient metabolism as described above from ingestion to generation of ATP. As of now several publications have revealed very intricate regulation of nutrient metabolism, where most of the regulatory factors are tied to each other bidirectionally, making it difficult to comprehend chronological sequence of events. Insulin hormone is the primary regulator of all nutrients' metabolism both in prandial and fasting states. Insulin exerts its effects directly and indirectly on enzymes involved in the three main cellular function processes; metabolic, inflammation and repair, and cell growth and regeneration. Final regulators that control the enzymatic functions through stimulation or suppression of a cell are nuclear receptors in especially farnesoid X receptor and peroxisome proliferator-activated receptor/RXR ligands, adiponectin, leptin, and adiponutrin. Insulin hormone has direct effect on these final modulators. Whereas blood glucose level, serum lipids, incretin hormones, bile acids in conjunction with microbiota are intermediary modulators which are controlled by lifestyle. The purpose of this review is to overview the key players in the pathogenesis of metabolic dysfunction-associated steatotic liver disease (MASLD) that help us understand the disease natural course, risk stratification, role of lifestyle and pharmacotherapy in each individual patient with MASLD to achieve personalized care and target the practice of precision medicine. PubMed and Google Scholar databases were used to identify publication related to metabolism of carbohydrate and fat in states of health and disease states; MASLD, cardiovascular disease and cancer. More than 1000 publications including original research and review papers were reviewed.
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Affiliation(s)
- Shahid Habib
- Department of Hepatology, Liver Institute PLLC, Tucson, AZ 85712, United States
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Bril F, Kalavalapalli S, Lomonaco R, Frye R, Godinez Leiva E, Cusi K. Insulin resistance is an integral feature of MASLD even in the presence of PNPLA3 variants. JHEP Rep 2024; 6:101092. [PMID: 39022386 PMCID: PMC11252529 DOI: 10.1016/j.jhepr.2024.101092] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/04/2024] [Revised: 03/29/2024] [Accepted: 04/03/2024] [Indexed: 07/20/2024] Open
Abstract
Background & Aims It has been postulated that carriers of PNPLA3 I148M (CG [Ile/Met] or GG [Met/Met]) develop metabolic dysfunction-associated steatotic liver disease (MASLD) in the absence of insulin resistance or metabolic syndrome. However, the relationship between insulin resistance and MASLD according to the PNPLA3 allele has not been carefully assessed. Methods A total of 204 participants were recruited and underwent PNPLA3 genotyping, an oral glucose tolerance test, liver proton magnetic resonance spectroscopy and percutaneous liver biopsy if diagnosed with MASLD. A subgroup of patients (n = 55) had an euglycemic hyperinsulinemic clamp with glucose tracer infusion. Results As expected, patients with the CG/GG genotype had worse intrahepatic triglyceride content and worse liver histology. However, regardless of PNPLA3 genotype, patients with a diagnosis of MASLD had severe whole-body insulin resistance (Matsuda index, an estimation of insulin resistance in glucose metabolic pathways) and fasting and postprandial adipose tissue insulin resistance (Adipo-IR index and free fatty acid suppression during the oral glucose tolerance test, respectively, as measures of insulin resistance in lipolytic metabolic pathways) compared to patients without MASLD. Moreover, for the same amount of liver fat accumulation, insulin resistance was similar in patients with genotypes CC vs. CG/GG. In multiple regression analyses, A1c and Adipo-IR were associated with the presence of MASLD and advanced liver fibrosis, independently of PNPLA3 genotype. Conclusions PNPLA3 variant carriers with MASLD are equally insulin resistant as non-carriers with MASLD at the level of the liver, muscle, and adipose tissue. This calls for reframing "PNPLA3 MASLD" as an insulin-resistant condition associated with increased hepatic susceptibility to metabolic insults, such as obesity or diabetes, wherein early identification and aggressive intervention are warranted to reverse metabolic dysfunction and prevent disease progression. Impact and implications It has been proposed that the PNPLA3 G allele is associated with the presence of metabolic dysfunction-associated steatotic liver disease (MASLD) in the absence of insulin resistance. However, our results suggest that regardless of PNPLA3 alleles, the presence of insulin resistance is necessary for the development of MASLD. This calls for reframing patients with "PNPLA3 MASLD" not as insulin sensitive, but on the contrary, as an insulin-resistant population with increased hepatic susceptibility to metabolic insults, such as obesity or diabetes.
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Affiliation(s)
- Fernando Bril
- Division of Endocrinology, Diabetes and Metabolism, University of Alabama at Birmingham. 510 20 Street South, FOT 825A, 35233, Birmingham, AL, USA
- Division of Endocrinology, Diabetes and Metabolism, University of Florida, Gainesville, FL, USA. 1600 Archer Road, Room H2, 32610, Gainesville, FL, USA
| | - Srilaxmi Kalavalapalli
- Division of Endocrinology, Diabetes and Metabolism, University of Florida, Gainesville, FL, USA. 1600 Archer Road, Room H2, 32610, Gainesville, FL, USA
| | - Romina Lomonaco
- Division of Endocrinology, Diabetes and Metabolism, University of Florida, Gainesville, FL, USA. 1600 Archer Road, Room H2, 32610, Gainesville, FL, USA
| | - Reginald Frye
- Center for Pharmacogenomics, University of Florida, Gainesville, FL, USA; Currently at College of Pharmacy, University of Tennessee Health Science Center, USA
| | - Eddison Godinez Leiva
- Division of Endocrinology, Diabetes and Metabolism, University of Florida, Gainesville, FL, USA. 1600 Archer Road, Room H2, 32610, Gainesville, FL, USA
| | - Kenneth Cusi
- Division of Endocrinology, Diabetes and Metabolism, University of Florida, Gainesville, FL, USA. 1600 Archer Road, Room H2, 32610, Gainesville, FL, USA
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Lee KJ, Moon JS, Lim JG, Huh H, Ahn JE, Kim L, Kim NY, Ko JS. PARVB and HSD17B13 variants are associated with nonalcoholic fatty liver disease in children. J Gastroenterol Hepatol 2024; 39:1172-1182. [PMID: 38418429 DOI: 10.1111/jgh.16521] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/09/2023] [Revised: 01/02/2024] [Accepted: 02/05/2024] [Indexed: 03/01/2024]
Abstract
BACKGROUND AND AIM The aim of this study was to investigate the comprehensive genetic effects of exploratory variants of LYPLAL1, GCKR, HSD17B13, TRIB1, APOC3, MBOAT7, and PARVB on pediatric nonalcoholic fatty liver disease in addition to the previously reported variants of TM6SF2, PNPLA3, and SAMM50 in Korean children. METHODS A prospective case-control study was conducted involving 309 patients diagnosed using ultrasound and 339 controls. Anthropometric measurements, liver function tests, and metabolic marker analysis were conducted, and fibrosis scores were calculated. Transient elastography was performed in 69 some patients with nonalcoholic fatty liver disease. TaqMan allelic discrimination assays were used for genotyping. The genetic risk scores were calculated using significant variants, namely, HSD17B13, PARVB, PNPLA3, SAMM50, and TM6SF2, to evaluate the additive effect. RESULTS Risk allele carriers of the PARVB variant showed significantly higher levels of aminotransferases, gamma-glutamyl transferase, alkaline phosphatase, pediatric nonalcoholic fatty liver disease fibrosis score, and aspartate aminotransferase/platelet ratio index. Individuals with a homozygous variant of HSD17B13 showed significantly lower levels of aminotransferase, gamma-glutamyl transferase, liver stiffness measurement, and aspartate aminotransferase/platelet ratio index than those with other genotypes. These parameters did not significantly differ among other variants of LYPLAL1, GCKR, TRIB1, APOC3, and MBOAT7. The genetic risk scores was identified as an independent risk factor for nonalcoholic fatty liver disease and had a positive association with severity. CONCLUSION HSD17B13 has protective effects on the severity of pediatric nonalcoholic fatty liver disease. Variants of HSD17B13, PARVB, PNPLA3, SAMM50, and TM6SF2 had an additive effect on nonalcoholic fatty liver disease.
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Affiliation(s)
- Kyung Jae Lee
- Department of Pediatrics, Seoul National University College of Medicine, Seoul, Korea
- Department of Pediatrics, Hallym University Sacred Heart Hospital, Anyang, Korea
| | - Jin Soo Moon
- Department of Pediatrics, Seoul National University College of Medicine, Seoul, Korea
| | - Jin Gyu Lim
- Department of Pediatrics, Seoul National University College of Medicine, Seoul, Korea
| | - Homin Huh
- Department of Pediatrics, Seoul National University College of Medicine, Seoul, Korea
| | - Jeong Eun Ahn
- Department of Pediatrics, Seoul National University College of Medicine, Seoul, Korea
| | - Lia Kim
- Department of Pediatrics, Seoul National University College of Medicine, Seoul, Korea
| | - Nan Young Kim
- Hallym Institute of Translational Genomics & Bioinformatics, Hallym University Medical Center, Anyang, Korea
| | - Jae Sung Ko
- Department of Pediatrics, Seoul National University College of Medicine, Seoul, Korea
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14
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Caddeo A, Spagnuolo R, Maurotti S. MBOAT7 in liver and extrahepatic diseases. Liver Int 2023; 43:2351-2364. [PMID: 37605540 DOI: 10.1111/liv.15706] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/24/2023] [Revised: 07/28/2023] [Accepted: 08/10/2023] [Indexed: 08/23/2023]
Abstract
MBOAT7 is a protein anchored to endomembranes by several transmembrane domains. It has a catalytic dyad involved in remodelling of phosphatidylinositol with polyunsaturated fatty acids. Genetic variants in the MBOAT7 gene have been associated with the entire spectrum of non-alcoholic fatty liver (NAFLD), recently redefined as metabolic dysfunction-associated fatty liver disease (MAFLD) and, lately, steatotic liver disease (SLD), and to an increasing number of extrahepatic conditions. In this review, we will (a) elucidate the molecular mechanisms by which MBOAT7 loss-of-function predisposes to MAFLD and neurodevelopmental disorders and (b) discuss the growing number of genetic studies linking MBOAT7 to hepatic and extrahepatic diseases. MBOAT7 complete loss of function causes severe changes in brain development resulting in several neurological manifestations. Lower MBOAT7 hepatic expression at both the mRNA and protein levels, due to missense nucleotide polymorphisms (SNPs) in the locus containing the MBOAT7 gene, affects specifically metabolic and viral diseases in the liver from simple steatosis to hepatocellular carcinoma, and potentially COVID-19 disease. This body of evidence shows that phosphatidylinositol remodelling is a key factor for human health.
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Affiliation(s)
- Andrea Caddeo
- Department of Biomedical Sciences, Unit of Oncology and Molecular Pathology, University of Cagliari, Cagliari, Italy
| | - Rocco Spagnuolo
- Department of Health Sciences, University Magna Graecia, Catanzaro, Italy
| | - Samantha Maurotti
- Department of Experimental and Clinical Medicine, Magna Graecia University, Catanzaro, Italy
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15
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Buchynskyi M, Oksenych V, Kamyshna I, Vari SG, Kamyshnyi A. Genetic Predictors of Comorbid Course of COVID-19 and MAFLD: A Comprehensive Analysis. Viruses 2023; 15:1724. [PMID: 37632067 PMCID: PMC10459448 DOI: 10.3390/v15081724] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2023] [Revised: 07/26/2023] [Accepted: 08/10/2023] [Indexed: 08/27/2023] Open
Abstract
Metabolic-associated fatty liver disease (MAFLD) and its potential impact on the severity of COVID-19 have gained significant attention during the pandemic. This review aimed to explore the genetic determinants associated with MAFLD, previously recognized as non-alcoholic fatty liver disease (NAFLD), and their potential influence on COVID-19 outcomes. Various genetic polymorphisms, including PNPLA3 (rs738409), GCKR (rs780094), TM6SF2 (rs58542926), and LYPLAL1 (rs12137855), have been investigated in relation to MAFLD susceptibility and progression. Genome-wide association studies and meta-analyses have revealed associations between these genetic variants and MAFLD risk, as well as their effects on lipid metabolism, glucose regulation, and liver function. Furthermore, emerging evidence suggests a possible connection between these MAFLD-associated polymorphisms and the severity of COVID-19. Studies exploring the association between indicated genetic variants and COVID-19 outcomes have shown conflicting results. Some studies observed a potential protective effect of certain variants against severe COVID-19, while others reported no significant associations. This review highlights the importance of understanding the genetic determinants of MAFLD and its potential implications for COVID-19 outcomes. Further research is needed to elucidate the precise mechanisms linking these genetic variants to disease severity and to develop gene profiling tools for the early prediction of COVID-19 outcomes. If confirmed as determinants of disease severity, these genetic polymorphisms could aid in the identification of high-risk individuals and in improving the management of COVID-19.
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Affiliation(s)
- Mykhailo Buchynskyi
- Department of Microbiology, Virology, and Immunology, I. Horbachevsky Ternopil National Medical University, 46001 Ternopil, Ukraine
| | - Valentyn Oksenych
- Broegelmann Research Laboratory, Department of Clinical Science, University of Bergen, 5020 Bergen, Norway
| | - Iryna Kamyshna
- Department of Medical Rehabilitation, I. Horbachevsky Ternopil National Medical University, 46001 Ternopil, Ukraine
| | - Sandor G. Vari
- International Research and Innovation in Medicine Program, Cedars–Sinai Medical Center, Los Angeles, CA 90048, USA
| | - Aleksandr Kamyshnyi
- Department of Microbiology, Virology, and Immunology, I. Horbachevsky Ternopil National Medical University, 46001 Ternopil, Ukraine
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Yenilmez B, Harney S, DiMarzio C, Kelly M, Min K, Echeverria D, Bramato BM, Jackson SO, Reddig K, Kim JK, Khvorova A, Czech MP. Dual targeting of hepatocyte DGAT2 and stellate cell FASN alleviates nonalcoholic steatohepatitis in mice. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.07.05.547848. [PMID: 37461560 PMCID: PMC10350091 DOI: 10.1101/2023.07.05.547848] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 07/25/2023]
Abstract
Nonalcoholic steatohepatitis (NASH) is a malady of multiple cell types associated with hepatocyte triglyceride (TG) accumulation, macrophage inflammation, and stellate cell-induced fibrosis, with no approved therapeutics yet available. Here, we report that stellate cell fatty acid synthase (FASN) in de novo lipogenesis drives the autophagic flux that is required for stellate cell activation and fibrotic collagen production. Further, we employ a dual targeting approach to NASH that selectively depletes collagen through selective stellate cell knockout of FASN (using AAV9-LRAT Cre in FASNfl/fl mice), while lowering hepatocyte triglyceride by depleting DGAT2 with a GalNac-conjugated, fully chemically modified siRNA. DGAT2 silencing in hepatocytes alone or in combination with stellate cell FASNKO reduced liver TG accumulation in a choline-deficient NASH mouse model, while FASNKO in hepatocytes alone (using AAV8-TBG Cre in FASNfl/fl mice) did not. Neither hepatocyte DGAT2 silencing alone nor FASNKO in stellate cells alone decreased fibrosis (total collagen), while loss of both DGAT2 plus FASN caused a highly significant attenuation of NASH. These data establish proof of concept that dual targeting of DGAT2 plus FASN alleviates NASH progression in mice far greater than targeting either gene product alone.
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Affiliation(s)
- Batuhan Yenilmez
- Program in Molecular Medicine, University of Massachusetts Chan Medical School, Worcester, MA, USA
| | - Shauna Harney
- Program in Molecular Medicine, University of Massachusetts Chan Medical School, Worcester, MA, USA
| | - Chloe DiMarzio
- Program in Molecular Medicine, University of Massachusetts Chan Medical School, Worcester, MA, USA
| | - Mark Kelly
- Program in Molecular Medicine, University of Massachusetts Chan Medical School, Worcester, MA, USA
| | - Kyounghee Min
- Program in Molecular Medicine, University of Massachusetts Chan Medical School, Worcester, MA, USA
| | - Dimas Echeverria
- Program in Molecular Medicine, University of Massachusetts Chan Medical School, Worcester, MA, USA
- RNA Therapeutics Institute, University of Massachusetts Chan Medical School, Worcester, MA, USA
| | - Brianna M. Bramato
- Program in Molecular Medicine, University of Massachusetts Chan Medical School, Worcester, MA, USA
- RNA Therapeutics Institute, University of Massachusetts Chan Medical School, Worcester, MA, USA
| | - Samuel O. Jackson
- Program in Molecular Medicine, University of Massachusetts Chan Medical School, Worcester, MA, USA
- RNA Therapeutics Institute, University of Massachusetts Chan Medical School, Worcester, MA, USA
| | - Keith Reddig
- Department of Radiology, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA
| | - Jason K. Kim
- Program in Molecular Medicine, University of Massachusetts Chan Medical School, Worcester, MA, USA
- Division of Endocrinology, Metabolism, and Diabetes, Department of Medicine, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA
| | - Anastasia Khvorova
- Program in Molecular Medicine, University of Massachusetts Chan Medical School, Worcester, MA, USA
- RNA Therapeutics Institute, University of Massachusetts Chan Medical School, Worcester, MA, USA
| | - Michael P. Czech
- Program in Molecular Medicine, University of Massachusetts Chan Medical School, Worcester, MA, USA
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17
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Xu X, Xu H, Liu X, Zhang S, Cao Z, Qiu L, Du X, Liu Y, Wang G, Zhang L, Zhang Y, Zhang J. MBOAT7 rs641738 (C>T) is associated with NAFLD progression in men and decreased ASCVD risk in elder Chinese population. Front Endocrinol (Lausanne) 2023; 14:1199429. [PMID: 37424875 PMCID: PMC10324031 DOI: 10.3389/fendo.2023.1199429] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/03/2023] [Accepted: 06/05/2023] [Indexed: 07/11/2023] Open
Abstract
Background and aim The MBOAT7 rs641738 (C>T) variant has demonstrated an association with non-alcoholic fatty liver disease (NAFLD) in both adult and pediatric patients, while few studies have been conducted in elderly populations. Hence, a case-control study was undertaken to assess their correlation in elderly residents in a Beijing community. Materials and methods A total of 1,287 participants were included. Medical history, abdominal ultrasound, and laboratory tests were recorded. Liver fat content and fibrosis stage were detected by Fibroscan. Genotyping of genomic DNA was performed using the 96.96 genotyping integrated fluidics circuit. Results Of the recruited subjects, 638 subjects (56.60%) had NAFLD, and 398 subjects (35.28%) had atherosclerotic cardiovascular disease (ASCVD). T allele carriage was associated with higher ALT (p=0.005) and significant fibrosis in male NAFLD patients (p=0.005) compared to CC genotype. TT genotype was associated with reduced risk of metabolic syndrome (OR=0.589, 95%CI: 0.114-0.683, p=0.005) and type 2 diabetes (OR=0.804, 95%CI: 0.277-0.296, p=0.048) in NAFLD population when compared to the CC genotype. In addition, TT genotype was also associated with reduced risk of ASCVD (OR=0.570, 95%CI:0.340-0.953, p=0.032) and less obesity (OR=0.545, 95%CI: 0.346-0.856, p=0.008) in the whole population. Conclusion MBOAT7 rs641738 (C>T) variant was associated with fibrosis in male NAFLD patients. The variant also reduced risk of metabolic traits and type 2 diabetes in NAFLD and ASCVD risk in Chinese elders.
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Affiliation(s)
- Xiaoyi Xu
- The Third Unit, The Department of Hepatology, Beijing Youan Hospital, Capital Medical University, Beijing, China
- Beijing Institute of Hepatology, Beijing Youan Hospital, Capital Medical University, Beijing, China
| | - Hangfei Xu
- The Third Unit, The Department of Hepatology, Beijing Youan Hospital, Capital Medical University, Beijing, China
- Beijing Institute of Hepatology, Beijing Youan Hospital, Capital Medical University, Beijing, China
| | - Xiaohui Liu
- The Third Unit, The Department of Hepatology, Beijing Youan Hospital, Capital Medical University, Beijing, China
| | - Shuang Zhang
- The Third Unit, The Department of Hepatology, Beijing Youan Hospital, Capital Medical University, Beijing, China
- Menkuang Hospital, Beijing Jingmei Group General Hospital, Beijing, China
| | - Zhenhuan Cao
- The Third Unit, The Department of Hepatology, Beijing Youan Hospital, Capital Medical University, Beijing, China
| | - Lixia Qiu
- The Third Unit, The Department of Hepatology, Beijing Youan Hospital, Capital Medical University, Beijing, China
| | - Xiaofei Du
- The Third Unit, The Department of Hepatology, Beijing Youan Hospital, Capital Medical University, Beijing, China
| | - Yali Liu
- The Third Unit, The Department of Hepatology, Beijing Youan Hospital, Capital Medical University, Beijing, China
| | - Gang Wang
- Menkuang Hospital, Beijing Jingmei Group General Hospital, Beijing, China
| | - Li Zhang
- Menkuang Hospital, Beijing Jingmei Group General Hospital, Beijing, China
| | - Yang Zhang
- The Third Unit, The Department of Hepatology, Beijing Youan Hospital, Capital Medical University, Beijing, China
- Beijing Institute of Hepatology, Beijing Youan Hospital, Capital Medical University, Beijing, China
| | - Jing Zhang
- The Third Unit, The Department of Hepatology, Beijing Youan Hospital, Capital Medical University, Beijing, China
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18
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Ajmera V, Wang N, Xu H, Liu CT, Long MT. Longitudinal association between overweight years, polygenic risk and NAFLD, significant fibrosis and cirrhosis. Aliment Pharmacol Ther 2023; 57:1143-1150. [PMID: 36924053 PMCID: PMC10178778 DOI: 10.1111/apt.17452] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/19/2022] [Revised: 11/06/2023] [Accepted: 02/23/2023] [Indexed: 03/18/2023]
Abstract
BACKGROUND Adiposity amplifies the genetic risk of non-alcoholic fatty liver disease (NAFLD). AIM We evaluated the association between overweight-years, a cumulative exposure based on the product of the duration and severity of excess body weight (body mass index (BMI) ≥ 25 kg/m2 ), and genetic risk on liver fat and fibrosis. METHODS This is a longitudinal analysis derived from a prospective cohort of adults in the Framingham Heart Study who underwent genotyping and vibration-controlled-transient-elastography with controlled attenuation parameter. Univariable and multivariable linear and logistic regression analyses were used to assess the association between overweight-years and liver fat and fibrosis. The association between genetic variants of liver fat (PNPLA3, TM6SF2, GCKR) and fibrosis (PNPLA3, TM6SF2, HSD17B13) was also assessed using a polygenic risk score. RESULTS Our sample included 2478 participants (54% women) with mean age and BMI of 40 (±8.5) years and 26.5(±5.1) kg/m2 , respectively. The mean follow-up was 14(±0.9) years, and each participant underwent three study visits. The prevalence of NAFLD was 28.3% (n = 700), and 207 (8.4%) had clinically significant fibrosis. In age-, sex- and diabetes-adjusted multivariable analyses, overweight-years (per SD) had a strong association with NAFLD (aOR 3.53 [95% CI: 3.10-4.02], p < 0.001), clinically significant fibrosis (aOR 1.60 [95% CI: 1.40-1.84], p < 0.001) and cirrhosis (aOR 1.81 [95% CI: 1.38-2.37], p < 0.001). High-polygenic risk was significantly associated with liver fat and clinically significant fibrosis (p < 0.05). CONCLUSION Overweight-years is strongly associated with NAFLD and clinically significant fibrosis and combined with polygenic risk may assist in defining the trajectory of NAFLD.
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Affiliation(s)
- Veeral Ajmera
- NAFLD Research Center, Division of Gastroenterology, University of California at San Diego, La Jolla, California, USA
- Division of Gastroenterology, University of California at San Diego, La Jolla, California, USA
| | - Na Wang
- Biostatistics and Epidemiology Data Analytics Center, Boston University School of Public Health, Boston, Massachusetts, USA
| | - Hanfei Xu
- Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts, USA
| | - Ching-Ti Liu
- Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts, USA
| | - Michelle T. Long
- Section of Gastroenterology, Boston Medical Center, Boston University School of Medicine, Boston, Massachusetts, USA
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19
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Sohal A, Chaudhry H, Kowdley KV. Genetic Markers Predisposing to Nonalcoholic Steatohepatitis. Clin Liver Dis 2023; 27:333-352. [PMID: 37024211 DOI: 10.1016/j.cld.2023.01.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/08/2023]
Abstract
The growing prevalence of nonalcoholic fatty liver disease (NAFLD) has sparked interest in understanding genetics and epigenetics associated with the development and progression of the disease. A better understanding of the genetic factors related to progression will be beneficial in the risk stratification of patients. These genetic markers can also serve as potential therapeutic targets in the future. In this review, we focus on the genetic markers associated with the progression and severity of NAFLD.
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Affiliation(s)
- Aalam Sohal
- Liver Institute Northwest, 3216 Northeast 45th Place Suite 212, Seattle, WA 98105, USA
| | - Hunza Chaudhry
- Department of Internal Medicine, UCSF Fresno, 155 North Fresno Street, Fresno, CA 93722, USA
| | - Kris V Kowdley
- Liver Institute Northwest, 3216 Northeast 45th Place Suite 212, Seattle, WA 98105, USA; Elson S. Floyd College of Medicine, Washington State University, WA, USA.
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20
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Koo BK, Lee H, Kwak SH, Lee DH, Park JH, Kim W. Long-Term Effect of PNPLA3 on the Aggravation of Nonalcoholic Fatty Liver Disease in a Biopsy-Proven Cohort. Clin Gastroenterol Hepatol 2023; 21:1105-1107.e3. [PMID: 35189385 DOI: 10.1016/j.cgh.2022.02.026] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/10/2022] [Revised: 02/12/2022] [Accepted: 02/15/2022] [Indexed: 02/07/2023]
Abstract
The PNPLA3 rs738409 G allele increases the risk of not only nonalcoholic fatty liver disease (NAFLD) but also nonalcoholic steatohepatitis (NASH) or fibrosis.1 It also affects the prognosis of patients with NAFLD in specific conditions. After liver transplantation, patients with NAFLD carrying the rs738409 GG genotype have a higher risk of graft steatosis2 or development of hepatocellular carcinoma.3 In addition, rs738409 modifies the effects of medical intervention: patients with NAFLD carrying the GG genotype showed a lower effect of omega-3 polyunsaturated fatty acid treatment on the reduction of liver fat;4 in contrast, they were more sensitive to the beneficial effects of lifestyle modifications.5,6.
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Affiliation(s)
- Bo Kyung Koo
- Division of Endocrinology, Department of Internal Medicine, Seoul Metropolitan Government Boramae Medical Center, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Hyunsuk Lee
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Soo-Heon Kwak
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Dong Hyeon Lee
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Seoul National University College of Medicine, Seoul Metropolitan Government Boramae Medical Center, Seoul, Republic of Korea
| | - Jeong Hwan Park
- Department of Pathology, Seoul National University College of Medicine, Seoul Metropolitan Government Boramae Medical Center, Seoul, Republic of Korea
| | - Won Kim
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Seoul National University College of Medicine, Seoul Metropolitan Government Boramae Medical Center, Seoul, Republic of Korea.
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21
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Son H, Koo BK, Joo SK, Lee DH, Jang H, Park JH, Chang MS, Kim W. PNPLA3 genotypes modify the adverse effect of the total energy intake on high-risk nonalcoholic steatohepatitis development. Am J Clin Nutr 2023; 117:910-917. [PMID: 36878430 DOI: 10.1016/j.ajcnut.2023.02.024] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2022] [Revised: 02/07/2023] [Accepted: 02/27/2023] [Indexed: 03/07/2023] Open
Abstract
BACKGROUND The relationship between diet and risk genotypes in nonalcoholic steatohepatitis (NASH) development and fibrosis progression in patients with nonalcoholic fatty liver disease (NAFLD) remains unclear. OBJECTIVE We aimed to investigate the effects of diet on NASH development and fibrosis progression in patients with NAFLD stratified by the PNPLA3 genotype. METHODS We performed a prospective study in a cohort of patients with biopsy-confirmed NAFLD. Histologic deterioration was obtained using serial transient elastography at every 1 or 2 y. The primary outcome was fibrosis progression, and the secondary outcome was development of high-risk NASH, defined as FibroScan-aspartate aminotransferase score ≥0.67 during the follow-up of patients with nonalcoholic fatty liver at the baseline. Dietary intake was evaluated using a semiquantitative food frequency questionnaire. RESULTS The primary outcome was observed in 42 (29.0%) of the 145 patients during a median follow-up of 49 mo; neither the total energy intake nor each macronutrient intake significantly affected the primary outcome occurrence. Conversely, the total energy intake (HR per 1-SD: 3.03; 95% CI: 1.31, 7.01) and the PNPLA3 rs738409 genotype [HR per 1 risk allele (G): 2.06; 95% CI: 1.11, 3.83)] were independent risk factors for high-risk NASH. The significant interaction between the total energy intake and PNPLA3 genotype was noted in developing high-risk NASH (P = 0.044). As the number of PNPLA3 risk alleles decreased, the effect of the total energy intake on high-risk NASH increased; the HR per 1-SD increment in total energy intake was 1.52 (95% CI: 0.42, 5.42), 3.54 (95% CI: 1.23, 10.18), and 8.27 (95% CI: 1.20, 57.23) for the GG, CG, and CC genotypes, respectively. CONCLUSIONS The total energy intake adversely affected the development of high-risk NASH in patients with biopsy-confirmed NAFLD. The effect was more prominent in patients without the PNPLA3 risk allele, highlighting the importance of personalized dietary interventions in NAFLD treatment.
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Affiliation(s)
- Heejun Son
- Division of Endocrinology, Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea
| | - Bo Kyung Koo
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea; Division of Endocrinology, Department of Internal Medicine, Seoul Metropolitan Government Boramae Medical Center, Seoul, Korea
| | - Sae Kyung Joo
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Seoul Metropolitan Government Boramae Medical Center, Seoul, Korea
| | - Dong Hyeon Lee
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Seoul Metropolitan Government Boramae Medical Center, Seoul, Korea
| | - Heejoon Jang
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Seoul Metropolitan Government Boramae Medical Center, Seoul, Korea
| | - Jeong Hwan Park
- Department of Pathology, Seoul National University College of Medicine, Seoul Metropolitan Government Boramae Medical Center, Seoul, Korea
| | - Mee Soo Chang
- Department of Pathology, Seoul National University College of Medicine, Seoul Metropolitan Government Boramae Medical Center, Seoul, Korea
| | - Won Kim
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea; Division of Gastroenterology and Hepatology, Department of Internal Medicine, Seoul Metropolitan Government Boramae Medical Center, Seoul, Korea.
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Mohamed Fteah A, Abdel Rahim A, Ahmed AbdelHady A, Shawky H, A Elrefaiy M, Mamdouh Aly D. Association of PNPLA3 (rs738409) & TM6SF2 (rs58542926) and ATG16L1 (rs2241880) genetic variants with susceptibility to hepatocellular carcinoma in a group of Egyptian patients with HCV-induced liver cirrhosis. Tumour Virus Res 2023; 15:200256. [PMID: 36804832 PMCID: PMC9975679 DOI: 10.1016/j.tvr.2023.200256] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2022] [Revised: 01/16/2023] [Accepted: 02/10/2023] [Indexed: 02/17/2023] Open
Affiliation(s)
| | - Ali Abdel Rahim
- Hepato-gastroentrology Department - Theodor Bilharz Research Institute, Egypt
| | | | - Hanan Shawky
- Clinical Chemistry Department - Theodor Bilharz Research Institute, Egypt
| | - Mohamed A Elrefaiy
- Hepato-gastroentrology Department - Theodor Bilharz Research Institute, Egypt
| | - Doaa Mamdouh Aly
- Clinical Chemistry Department - Theodor Bilharz Research Institute, Egypt
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23
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Sulaiman SA, Dorairaj V, Adrus MNH. Genetic Polymorphisms and Diversity in Nonalcoholic Fatty Liver Disease (NAFLD): A Mini Review. Biomedicines 2022; 11:106. [PMID: 36672614 PMCID: PMC9855725 DOI: 10.3390/biomedicines11010106] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2022] [Revised: 12/13/2022] [Accepted: 12/27/2022] [Indexed: 01/03/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is a common liver disease with a wide spectrum of liver conditions ranging from hepatic steatosis to nonalcoholic steatohepatitis (NASH), fibrosis, cirrhosis, and hepatocellular carcinoma. The prevalence of NAFLD varies across populations, and different ethnicities have specific risks for the disease. NAFLD is a multi-factorial disease where the genetics, metabolic, and environmental factors interplay and modulate the disease's development and progression. Several genetic polymorphisms have been identified and are associated with the disease risk. This mini-review discussed the NAFLD's genetic polymorphisms and focusing on the differences in the findings between the populations (diversity), including of those reports that did not show any significant association. The challenges of genetic diversity are also summarized. Understanding the genetic contribution of NAFLD will allow for better diagnosis and management explicitly tailored for the various populations.
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Affiliation(s)
- Siti Aishah Sulaiman
- UKM Medical Molecular Biology Institute (UMBI), Universiti Kebangsaan Malaysia (UKM), Jalan Yaa’cob Latiff, Cheras, Kuala Lumpur 56000, Malaysia; (V.D.); (M.N.H.A.)
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Cavalcante LN, Porto J, Mazo D, Longatto-Filho A, Stefano JT, Lyra AC, Carrilho FJ, Reis RM, Alves VAF, Sanyal AJ, Oliveira CP. African genetic ancestry is associated with lower frequency of PNPLA3 G allele in non-alcoholic fatty liver in an admixed population. Ann Hepatol 2022; 27:100728. [PMID: 35710086 DOI: 10.1016/j.aohep.2022.100728] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/10/2022] [Revised: 05/06/2022] [Accepted: 05/19/2022] [Indexed: 02/04/2023]
Abstract
INTRODUCTION AND OBJECTIVES PNPLA3 (rs738409) and TM6SF2 (rs58542926) variants, interindividual and ethnic differences may be risk factors for non-alcoholic fatty liver disease (NAFLD). The PNPLA3 G allele is associated with worse NAFLD evolution in Hispanics and Caucasians. TM6SF2 is associated with hypertriglyceridemia, NAFLD, and cardiovascular disease. We aimed to evaluate the association between genetic ancestry by Ancestry Informative Markers (AIM), PNPLA3 and TM6SF2 polymorphisms in patients with biopsy-proven NAFLD in an admixed population. METHODS We included adults with biopsy-proven NAFLD and excluded patients with the presence of other chronic liver disease, alcohol intake >100g/week, HIV, drug-induced fatty liver disease, or liver transplantation. We classified NAFLD using the Non-Alcoholic Steatohepatitis Clinical Research Network (NASH-CRN) histological scoring system. The PNPLA3 (rs738409 c.444C>G) and TM6SF2 (rs58542926 c.449C>T) genotyping were performed by RT-PCR. Genetic ancestry was determined using 46 insertion-deletion AIM; α<0.05 was considered significant. RESULTS A total of 248 patients with NAFLD were enrolled [34 with simple steatosis (NAFL); 214 with NASH]. Overall, we detected a greater European ancestry contribution (0.645), followed by African (0.173), Amerindian (0.095), and East Asian (0.087) ancestry contribution, without differences between NAFL and NASH patients. However, we found a higher African genetic ancestry contribution among patients with NAFL who had the PNPLA3 C/C genotype than those with the G allele (0.216 ± 0.205 versus 0.105 ± 0.101, respectively; p=0.047). Ancestry contributions did not differ among TM6SF2 genotypes. CONCLUSION Among NAFL patients, greater African genetic ancestry was associated to a lower frequency of the PNPLA3 G allele, demonstrating a possible NASH ancestry-related protective factor.
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Affiliation(s)
| | - Jun Porto
- Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos-SP, Brazil
| | - Daniel Mazo
- University of Sao Paulo, School of Medicine, Sao Paulo-SP, Brazil; Laboratory of Clinical and Experimental Gastroenterology (LIM-07), Division of Clinical Gastroenterology and Hepatology, Department of Gastroenterology, Faculty of Medicine, University of São Paulo, São Paulo, SP, Brazil
| | - Adhemar Longatto-Filho
- University of Sao Paulo, School of Medicine, Sao Paulo-SP, Brazil; Department of Pathology (LIM-14), Faculty of Medicine, University of São Paulo, Brazil; Life and Health Sciences Research Institute (ICVS), Medical School, University of Minho, Braga, Portugal; ICVS/3B's-PT Government Associate Laboratory, Braga, Guimarães, Portugal
| | - José Tadeu Stefano
- University of Sao Paulo, School of Medicine, Sao Paulo-SP, Brazil; Laboratory of Clinical and Experimental Gastroenterology (LIM-07), Division of Clinical Gastroenterology and Hepatology, Department of Gastroenterology, Faculty of Medicine, University of São Paulo, São Paulo, SP, Brazil
| | - Andre Castro Lyra
- Federal University of Bahia, School of Medicine, Gastroenterology and Hepatology Services & Salvador-BA, Brazil
| | - Flair Jose Carrilho
- University of Sao Paulo, School of Medicine, Sao Paulo-SP, Brazil; Laboratory of Clinical and Experimental Gastroenterology (LIM-07), Division of Clinical Gastroenterology and Hepatology, Department of Gastroenterology, Faculty of Medicine, University of São Paulo, São Paulo, SP, Brazil
| | - Rui Manuel Reis
- Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos-SP, Brazil; Laboratory of Clinical and Experimental Gastroenterology (LIM-07), Division of Clinical Gastroenterology and Hepatology, Department of Gastroenterology, Faculty of Medicine, University of São Paulo, São Paulo, SP, Brazil; Department of Pathology (LIM-14), Faculty of Medicine, University of São Paulo, Brazil; Life and Health Sciences Research Institute (ICVS), Medical School, University of Minho, Braga, Portugal
| | - Venâncio A F Alves
- University of Sao Paulo, School of Medicine, Sao Paulo-SP, Brazil; Department of Pathology (LIM-14), Faculty of Medicine, University of São Paulo, Brazil
| | - Arun J Sanyal
- Institute of Liver Disease and Metabolic Health; Interim Chair, Div. of Gastroenterology; Virginia Commonwealth University, USA
| | - Claudia P Oliveira
- University of Sao Paulo, School of Medicine, Sao Paulo-SP, Brazil; Laboratory of Clinical and Experimental Gastroenterology (LIM-07), Division of Clinical Gastroenterology and Hepatology, Department of Gastroenterology, Faculty of Medicine, University of São Paulo, São Paulo, SP, Brazil
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Youssef SS, Abbas EAER, Elfiky AM, Seif S, Nabeel MM, Shousha HI, Abdelaziz AO. The impact of polymorphism in PNPLA3 and TM6SF2 genes on the susceptibility and survival of hepatitis C-related hepatocellular carcinoma. EGYPTIAN LIVER JOURNAL 2022; 12:56. [DOI: 10.1186/s43066-022-00212-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2022] [Accepted: 08/28/2022] [Indexed: 12/02/2022] Open
Abstract
Abstract
Background
Genetic variants of Patatin-like phospholipase domain-containing protein 3 (PNPLA3) and transmembrane 6 superfamily member 2 (TM6SF2) genes have been reported with the development of hepatocellular carcinoma (HCC). This study aims to explore the role of The PNPLA3 rs738409 and TM6SF2 rs58542926 single-nucleotide polymorphisms (SNPs) on the incidence and survival of HCV-induced HCC in Egyptians.
Methods and results
This case-control study included (120) HCC and (144) hepatitis C virus (HCV) patients. Baseline clinical, laboratory, tumor characteristics data, HCC recurrence, and overall survival were collected. PNPLA3 rs738409 and TM6SF2 rs58542926 polymorphism were detected by TaqMan allelic discrimination assay. We found that HCC patients were significantly older with male predominance. A significant difference between the TT genotypes of TM6SF2 frequency was observed in HCC compared with HCV patients. Moreover, the T allele of TM6SF2 distributions revealed a significant contribution to the different stages of HCC (p=0.03). Both PNPLA3 rs738409 and TM6SF2 rs58542926 variants showed a significant relation with treatment response according to the modified RECIST criteria. Age and diabetes mellitus were the independent factors associated with the development of HCC by multivariate regression analysis.
Conclusions
TM6SF2 rs58542926 polymorphism, not PNPLA3 rs738409, could be implicated in the development of HCV-induced HCC and its progression.
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Advance of Serum Biomarkers and Combined Diagnostic Panels in Nonalcoholic Fatty Liver Disease. DISEASE MARKERS 2022; 2022:1254014. [PMID: 35811662 PMCID: PMC9259243 DOI: 10.1155/2022/1254014] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/07/2022] [Revised: 05/31/2022] [Accepted: 06/02/2022] [Indexed: 02/06/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD) affects approximately 25-30% population worldwide, which progresses from simple steatosis to nonalcoholic steatohepatitis (NASH), fibrosis, cirrhosis, and hepatocellular carcinoma, and has complications such as cardiovascular events. Liver biopsy is still the gold standard for the diagnosis of NAFLD, with some limitations, such as invasive, sampling deviation, and empirical judgment. Therefore, it is urgent to develop noninvasive diagnostic biomarkers. Currently, a large number of NAFLD-related serum biomarkers have been identified, including apoptosis, inflammation, fibrosis, adipokines, hepatokines, and omics biomarkers, which could effectively diagnose NASH and exclude patients with progressive fibrosis. We summarized serum biomarkers and combined diagnostic panels of NAFLD, to provide some guidance for the noninvasive diagnosis and further clinical studies.
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Varadharajan V, Massey WJ, Brown JM. Membrane-bound O-acyltransferase 7 (MBOAT7)-driven phosphatidylinositol remodeling in advanced liver disease. J Lipid Res 2022; 63:100234. [PMID: 35636492 PMCID: PMC9240865 DOI: 10.1016/j.jlr.2022.100234] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2022] [Revised: 05/12/2022] [Accepted: 05/16/2022] [Indexed: 01/21/2023] Open
Abstract
Advanced liver diseases account for approximately 2 million deaths annually worldwide. Roughly, half of liver disease-associated deaths arise from complications of cirrhosis and the other half driven by viral hepatitis and hepatocellular carcinoma. Unfortunately, the development of therapeutic strategies to treat subjects with advanced liver disease has been hampered by a lack of mechanistic understanding of liver disease progression and a lack of human-relevant animal models. An important advance has been made within the past several years, as several genome-wide association studies have discovered that an SNP near the gene encoding membrane-bound O-acyltransferase 7 (MBOAT7) is associated with severe liver diseases. This common MBOAT7 variant (rs641738, C>T), which reduces MBOAT7 expression, confers increased susceptibility to nonalcoholic fatty liver disease, alcohol-associated liver disease, and liver fibrosis in patients chronically infected with viral hepatitis. Recent studies in mice also show that Mboat7 loss of function can promote hepatic steatosis, inflammation, and fibrosis, causally linking this phosphatidylinositol remodeling enzyme to liver health in both rodents and humans. Herein, we review recent insights into the mechanisms by which MBOAT7-driven phosphatidylinositol remodeling influences liver disease progression and discuss how rapid progress in this area could inform drug discovery moving forward.
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Affiliation(s)
- Venkateshwari Varadharajan
- Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute Cleveland Clinic, Cleveland, OH, USA; Center for Microbiome and Human Health, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
| | - William J Massey
- Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute Cleveland Clinic, Cleveland, OH, USA; Center for Microbiome and Human Health, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
| | - J Mark Brown
- Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute Cleveland Clinic, Cleveland, OH, USA; Center for Microbiome and Human Health, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.
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Kang H, You HJ, Lee G, Lee SH, Yoo T, Choi M, Joo SK, Park JH, Chang MS, Lee DH, Kim W, Ko G. Interaction effect between NAFLD severity and high carbohydrate diet on gut microbiome alteration and hepatic de novo lipogenesis. Gut Microbes 2022; 14:2078612. [PMID: 35634707 PMCID: PMC9154801 DOI: 10.1080/19490976.2022.2078612] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is associated with high carbohydrate (HC) intake. We investigated whether the relationship between carbohydrate intake and NAFLD is mediated by interactions between gut microbial modulation, impaired insulin response, and hepatic de novo lipogenesis (DNL). Stool samples were collected from 204 Korean subjects with biopsy-proven NAFLD (n = 129) and without NAFLD (n = 75). The gut microbiome profiles were analyzed using 16S rRNA amplicon sequencing. Study subjects were grouped by the NAFLD activity score (NAS) and percentage energy intake from dietary carbohydrate. Hepatic DNL-related transcripts were also analyzed (n = 90). Data from the Korean healthy twin cohort (n = 682), a large sample of individuals without NAFLD, were used for comparison and validation. A HC diet rather than a low carbohydrate diet was associated with the altered gut microbiome diversity according to the NAS. Unlike individuals from the twin cohort without NAFLD, the abundances of Enterobacteriaceae and Ruminococcaceae were significantly different among the NAS subgroups in NAFLD subjects who consumed an HC diet. The addition of these two microbial families, along with Veillonellaceae, significantly improved the diagnostic performance of the predictive model, which was based on the body mass index, age, and sex to predict nonalcoholic steatohepatitis in the HC group. In the HC group, two crucial regulators of DNL (SIRT1 and SREBF2) were differentially expressed among the NAS subgroups. In particular, kernel causality analysis revealed a causal effect of the abundance of Enterobacteriaceae on SREBF2 upregulation and of the surrogate markers of insulin resistance on NAFLD activity in the HC group. Consuming an HC diet is associated with alteration in the gut microbiome, impaired glucose homeostasis, and upregulation of hepatic DNL genes, altogether contributing to NAFLD pathogenesis.
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Affiliation(s)
- Hyena Kang
- Department of Environmental Health Sciences, Graduate School of Public Health, Seoul National University, Republic of Korea
| | - Hyun Ju You
- Department of Environmental Health Sciences, Graduate School of Public Health, Seoul National University, Republic of Korea,Center for Human and Environmental Microbiome, Institute of Health and Environment, Seoul National University, Republic of Korea,Bio-MAX/N-Bio, Seoul National University, Seoul, Republic of Korea
| | - Giljae Lee
- Department of Environmental Health Sciences, Graduate School of Public Health, Seoul National University, Republic of Korea
| | - Seung Hyun Lee
- Department of Environmental Health Sciences, Graduate School of Public Health, Seoul National University, Republic of Korea
| | - Taekyung Yoo
- Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Murim Choi
- Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Sae Kyung Joo
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Seoul National University College of Medicine, Seoul Metropolitan Government Boramae Medical Center, Seoul, Republic of Korea
| | - Jeong Hwan Park
- Department of Pathology, Seoul National University College of Medicine, Seoul Metropolitan Government Boramae Medical Center, Seoul, Republic of Korea
| | - Mee Soo Chang
- Department of Pathology, Seoul National University College of Medicine, Seoul Metropolitan Government Boramae Medical Center, Seoul, Republic of Korea
| | - Dong Hyeon Lee
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Seoul National University College of Medicine, Seoul Metropolitan Government Boramae Medical Center, Seoul, Republic of Korea
| | - Won Kim
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Seoul National University College of Medicine, Seoul Metropolitan Government Boramae Medical Center, Seoul, Republic of Korea,CONTACT Won Kim Division of Gastroenterology and Hepatology, Department of Internal Medicine, Seoul National University College of Medicine, Seoul Metropolitan Government Boramae Medical Center, Seoul07061, Republic of Korea
| | - GwangPyo Ko
- Department of Environmental Health Sciences, Graduate School of Public Health, Seoul National University, Republic of Korea,Center for Human and Environmental Microbiome, Institute of Health and Environment, Seoul National University, Republic of Korea,Bio-MAX/N-Bio, Seoul National University, Seoul, Republic of Korea,KoBioLabs Inc, Seoul, Republic of Korea,GwangPyo Ko Department of Environmental Health Sciences, Graduate School of Public Health, Seoul National University, Seoul 08826, Republic of Korea
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De Vincentis A, Tavaglione F, Jamialahmadi O, Picardi A, Antonelli Incalzi R, Valenti L, Romeo S, Vespasiani-Gentilucci U. A Polygenic Risk Score to Refine Risk Stratification and Prediction for Severe Liver Disease by Clinical Fibrosis Scores. Clin Gastroenterol Hepatol 2022; 20:658-673. [PMID: 34091049 DOI: 10.1016/j.cgh.2021.05.056] [Citation(s) in RCA: 66] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/19/2021] [Revised: 05/16/2021] [Accepted: 05/31/2021] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS A polygenic risk score based on well-known genetic variants in PNPLA3, TM6SF2, MBOAT7, and GCKR predicts hepatic fat content (polygenic risk score-hepatic fat content [PRS-HFC]). Here, we hypothesized that the addition of PRS-HFC to clinical fibrosis scores may improve risk stratification and prediction of severe liver disease (SLD). METHODS We used data from 266,687 individuals in the UK Biobank, evaluating the incidence of cirrhosis, decompensated liver disease, hepatocellular carcinoma, and/or liver transplantation during a median follow-up period of 9 years. Nonalcoholic fatty liver disease fibrosis score, Fibrosis-4, aspartate aminotransferase-to-platelet ratio, BARD, and Forns scores, and PRS-HFC, were computed. All analyses were stratified according to the presence of diabetes, obesity, and a positive fatty liver index (≥60). RESULTS Unfavorable genetics (PRS-HFC, ≥0.396) further stratified the risk of SLD in subjects in intermediate-/high-risk classes of fibrosis scores, with a higher effect in those with metabolic risk factors, and the prediction was improved by integrating PRS-HFC (areas under the receiver operating characteristic increased for all scores with a P value of approximately 10-2 to 10-4, except for the aspartate aminotransferase-to-platelet ratio in the overall population and in subjects with obesity). PRS-HFC improved diagnostic accuracies and positive predictive values for SLD in intermediate-high clinical score risk classes. Risk stratification and prediction were not affected or were poorly affected by unfavorable genetics in subjects without metabolic risk factors. CONCLUSIONS Integration of genetics with clinical fibrosis scores refines individual risk and prediction for SLD, mainly in individuals at risk for nonalcoholic fatty liver disease. These data provide evidence from a prospective cohort that common genetic variants capture additional prognostic insights not conveyed by validated clinical/biochemical parameters.
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Affiliation(s)
- Antonio De Vincentis
- Internal Medicine Unit, Department of Internal Medicine and Geriatrics, Campus Bio-Medico University, Rome, Italy; Internal Medicine, Saint Camillus International University of Health and Medical Sciences, Rome, Italy
| | - Federica Tavaglione
- Clinical Medicine and Hepatology Unit, Department of Internal Medicine and Geriatrics, Campus Bio-Medico University, Rome, Italy; Department of Molecular and Clinical Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Oveis Jamialahmadi
- Department of Molecular and Clinical Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Antonio Picardi
- Clinical Medicine and Hepatology Unit, Department of Internal Medicine and Geriatrics, Campus Bio-Medico University, Rome, Italy
| | - Raffaele Antonelli Incalzi
- Internal Medicine Unit, Department of Internal Medicine and Geriatrics, Campus Bio-Medico University, Rome, Italy
| | - Luca Valenti
- Department of Pathophysiology and Transplantation, Università; degli Studi di Milano, Milano, Italy; Translational Medicine, Department of Transfusion Medicine and Hematology, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico Ca' Granda Ospedale Maggiore Policlinico, Milano, Italy
| | - Stefano Romeo
- Department of Molecular and Clinical Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; Clinical Nutrition Unit, Department of Medical and Surgical Science, Magna Graecia University, Catanzaro, Italy; Department of Cardiology, Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Umberto Vespasiani-Gentilucci
- Clinical Medicine and Hepatology Unit, Department of Internal Medicine and Geriatrics, Campus Bio-Medico University, Rome, Italy.
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Moon S, Chung GE, Joo SK, Park JH, Chang MS, Yoon JW, Koo BK, Kim W. A PNPLA3 Polymorphism Confers Lower Susceptibility to Incident Diabetes Mellitus in Subjects With Nonalcoholic Fatty Liver Disease. Clin Gastroenterol Hepatol 2022; 20:682-691.e8. [PMID: 33905771 DOI: 10.1016/j.cgh.2021.04.038] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2021] [Revised: 04/19/2021] [Accepted: 04/19/2021] [Indexed: 12/15/2022]
Abstract
BACKGROUND AND AIMS We investigated the association between the patatin-like phospholipase domain-containing-3 (PNPLA3) rs738409 genotype and the risk of diabetes mellitus (DM) using a biopsy-confirmed nonalcoholic fatty liver disease (NAFLD) cohort and a longitudinal observational cohort. METHODS Associations between genotypes and the prevalence of DM were evaluated with stratification according to the histological severity of NAFLD in the Boramae cohort (n = 706). A longitudinal cohort consisting of nondiabetic individuals with ≥2 health checkups was then selected to investigate the risk of incident DM according to the genotype (the GENIE cohort; n = 4998). RESULTS Among subjects with NAFLD in the Boramae cohort, the G allele was independently associated with a lower prevalence of DM in both NAFL (odds ratio [OR] per 1 allele, 0.66; 95% confidence interval [CI], 0.46-0.97) and nonalcoholic steatohepatitis (OR per 1 allele, 0.59; 95% CI, 0.38-0.92). This result was replicated in the longitudinal GENIE cohort. The G allele was associated with a lower risk of incident DM during the median follow-up of 60 months in subjects with NAFLD (hazard ratio, 0.65; 95% CI, 0.45-0.93). In contrast, G allele carriers without NAFLD showed higher odds for DM in the context of the Boramae cohort (OR, 2.44; 95% CI, 1.00-5.95). CONCLUSIONS These findings clarify conflicting results regarding the association between the PNPLA3 rs738409 genotype and the risk of DM, demonstrating a clear difference between subjects with and without NAFLD; this difference might be explained by the low metabolic risk in genetic NAFLD.
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Affiliation(s)
- Seoil Moon
- Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea; On behalf of the Innovative Target Exploration of NAFLD (ITEN) consortium
| | - Goh Eun Chung
- Department of Internal Medicine, Healthcare System Gangnam Center, Seoul National University Hospital, Seoul, Korea; On behalf of the Innovative Target Exploration of NAFLD (ITEN) consortium
| | - Sae Kyung Joo
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Seoul National University College of Medicine, Seoul Metropolitan Government Boramae Medical Center, Seoul, Korea; On behalf of the Innovative Target Exploration of NAFLD (ITEN) consortium
| | - Jeong Hwan Park
- Department of Pathology, Seoul National University College of Medicine, Seoul Metropolitan Government Boramae Medical Center, Seoul, Korea; On behalf of the Innovative Target Exploration of NAFLD (ITEN) consortium
| | - Mee Soo Chang
- Department of Pathology, Seoul National University College of Medicine, Seoul Metropolitan Government Boramae Medical Center, Seoul, Korea; On behalf of the Innovative Target Exploration of NAFLD (ITEN) consortium
| | - Ji Won Yoon
- Department of Internal Medicine, Healthcare System Gangnam Center, Seoul National University Hospital, Seoul, Korea; On behalf of the Innovative Target Exploration of NAFLD (ITEN) consortium
| | - Bo Kyung Koo
- Division of Endocrinology, Department of Internal Medicine, Seoul National University College of Medicine, Seoul Metropolitan Government Boramae Medical Center, Seoul, Korea; On behalf of the Innovative Target Exploration of NAFLD (ITEN) consortium.
| | - Won Kim
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Seoul National University College of Medicine, Seoul Metropolitan Government Boramae Medical Center, Seoul, Korea; On behalf of the Innovative Target Exploration of NAFLD (ITEN) consortium.
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Xue WY, Zhang L, Liu CM, Gao Y, Li SJ, Huai ZY, Dai J, Wang YY. Research progress on the relationship between TM6SF2 rs58542926 polymorphism and non-alcoholic fatty liver disease. Expert Rev Gastroenterol Hepatol 2022; 16:97-107. [PMID: 35057689 DOI: 10.1080/17474124.2022.2032661] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
INTRODUCTION nonalcoholic fatty liver disease is a common liver disease with a global average prevalence of about 25%. In addition to the incidence of NAFLD being related to obesity, diabetes, hyperlipidemia, etc., genetic factors also have an important impact on the incidence of NAFLD. AREAS COVERED Current experimental results and clinical studies show that the transmembrane 6 superfamily member 2 (TM6SF2) gene plays an important role in the pathogenesis of NAFLD. The research on genetic polymorphism of TM6SF2 gene mainly focuses on rs58542926 locus (rs58542926 c.449 C > T, p. Glu167Lys, E167K). The Mutations of this site might increase the risk of NAFLD in carriers. EXPERT OPINION The mutation of this site causes the disorder of triglyceride metabolism in the liver, which leads to the deposition of a large amount of lipids in the liver, and further induces the incidence of NAFLD. With the study of the mechanism of TM6SF2 gene polymorphism in the pathogenesis of NAFLD, it is helpful to understand the molecular mechanism of the pathogenesis of NAFLD, which has a great value for the treatment of NAFLD.
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Affiliation(s)
- Wan-Ying Xue
- School of Life Sciences, Bengbu Medical College, Bengbu, Anhui, China
| | - Li Zhang
- Department of Infectious Diseases, The First Affiliated Hospital of Bengbu Medical College, Bengbu, Anhui, China
| | - Chuan-Miao Liu
- Department of Infectious Diseases, The First Affiliated Hospital of Bengbu Medical College, Bengbu, Anhui, China
| | - Yu Gao
- School of Life Sciences, Bengbu Medical College, Bengbu, Anhui, China
| | - Shu-Jing Li
- School of Life Sciences, Bengbu Medical College, Bengbu, Anhui, China
| | - Zi-You Huai
- School of Life Sciences, Bengbu Medical College, Bengbu, Anhui, China
| | - Jing Dai
- School of Life Sciences, Bengbu Medical College, Bengbu, Anhui, China
| | - Yuan-Yuan Wang
- School of Life Sciences, Bengbu Medical College, Bengbu, Anhui, China
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Epidemiology and disease burden of non-alcoholic steatohepatitis in greater China: a systematic review. Hepatol Int 2022; 16:27-37. [DOI: 10.1007/s12072-021-10286-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/19/2021] [Accepted: 12/06/2021] [Indexed: 12/12/2022]
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Li XY, Liu Z, Li L, Wang HJ, Wang H. TM6SF2 rs58542926 is related to hepatic steatosis, fibrosis and serum lipids both in adults and children: A meta-analysis. Front Endocrinol (Lausanne) 2022; 13:1026901. [PMID: 36353245 PMCID: PMC9637980 DOI: 10.3389/fendo.2022.1026901] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/24/2022] [Accepted: 10/12/2022] [Indexed: 11/16/2022] Open
Abstract
BACKGROUND AND AIMS Findings about the associations between transmembrane 6 superfamily member 2 (TM6SF2) rs58542926 and nonalcoholic fatty liver disease have not been consistently replicated, particularly in steatosis and fibrosis. The present study aimed to investigate the associations between the rs58542926T allele and the spectrum of NAFLD and its related metabolic phenotypes. METHODS Systematic literature research was performed to analyse the associations between rs58542926 and the spectrum of NAFLD and its related metabolic phenotypes. A random effects meta-analysis with a dominant genetic model was applied. RESULTS Data from 123,800 individuals across 44 studies were included in the current meta-analysis.rs58542926 T allele was associated with an increased risk of NAFLD in both adults (OR=1.62; 95% CI: 1.40, 1.86) and children (OR=2.87; 95% CI: 1.85, 4.46). Children had a stronger association with NAFLD (P=0.01). rs58542926 T allele was also positively associated with steatosis progression (mean difference=0.22; 95% CI: 0.05, 0.39) and fibrosis stage (OR=1.50; 95% CI: 1.20, 1.88) in adults. The TM6SF2 rs58542926 T allele was positively associated with ALT in both adults and children (both P<0.01) and only with higher AST in adults (P<0.01). The rs58542926 T allele was negatively associated with serum total cholesterol (TC), low-density lipoprotein (LDL), and triglycerides (TGs) in both adults and children (all P<0.01).The serum level of TG was much lower in adults than in children (P<0.01). CONCLUSION TM6SF2 rs58542926 is involved in the entire spectrum of NAFLD and its related metabolic phenotype, and differences in serum lipid levels were observed between adults and children. SYSTEMATIC REVIEW REGISTRATION https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42021288163.
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Affiliation(s)
- Xue-Ying Li
- Department of Maternal and Child Health, School of Public Health, Peking University, Beijing, China
| | - Zheng Liu
- Department of Maternal and Child Health, School of Public Health, Peking University, Beijing, China
| | - Li Li
- Department of Endocrinology and Metabolism, Ningbo First Hospital, Ningbo, China
| | - Hai-Jun Wang
- Department of Maternal and Child Health, School of Public Health, Peking University, Beijing, China
| | - Hui Wang
- Department of Maternal and Child Health, School of Public Health, Peking University, Beijing, China
- *Correspondence: Hui Wang,
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Eshraghian A, Moasser E, Azarpira N, Fattahi MR, Nikeghbalian S, Malek-Hosseini SA, Geramizadeh B. Variations in TM6SF2, PCSK9 and PCSK7 genes and risk of hepatic steatosis after liver transplantation: a cross-sectional study. BMC Gastroenterol 2021; 21:458. [PMID: 34876018 PMCID: PMC8650293 DOI: 10.1186/s12876-021-02041-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/12/2021] [Accepted: 11/22/2021] [Indexed: 11/29/2022] Open
Abstract
Background Genetic abnormalities might have important role in pathogenesis of hepatic steatosis after liver transplantation. We aimed to investigate association between genetic variations in transmembrane 6 superfamily member 2 (TM6SF2) rs58542926, proprotein convertase subtilisin/kexin type 9 (PCSK9) rs505151 and proprotein convertase subtilisin/kexin type 7 (PCSK7) rs2277287 with hepatic steatosis in liver transplant recipients.
Methods In a cross-sectional study, adult (> 18 years) liver transplant recipients who were referred for their routine post-transplant follow-up between June 2018 and September 2018 were included in the study. Hepatic steatosis in transplant recipients was assessed by controlled attenuation parameter (CAP). Polymerase chain reaction-restriction fragment length polymorphism (PCR–RFLP) was used to study TM6SF2 rs58542926, PCSK7 rs2277287 and PCSK9 rs505151 genotypes. Results 107 liver transplant recipients were included. There was no association between different genotypes of PCSK9 rs505151 and PCSK7 rs2277287 with hepatic steatosis in liver transplant recipients (P value > 0.05). The presence of TT genotype of TM6SF2 rs58542926 was higher in patients with hepatic steatosis measured by CAP after liver transplantation. In patients with moderate and severe hepatic steatosis (grade 2 and 3 steatosis), AG + GG genotypes of PCSK9 rs505151 were more prevalent than AA genotype (OR 8.667; 95% CI 1.841–40.879; P value = 0.004) compared to patients with mild steatosis (grade 1). In multivariate regression model, AG + GG genotypes of PCSK9 rs505151 were associated with moderate and severe steatosis in liver transplant recipients (OR 5.747; 95% CI 1.086–30.303; P value = 0.040). Conclusions Genetic variations in TM6SF2 rs58542926 and PCSK9 rs505151 might be associated with hepatic steatosis in liver transplant recipients.
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Affiliation(s)
- Ahad Eshraghian
- Shiraz Transplant Center, Abu-Ali Sina Hospital, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Elham Moasser
- Transplant Research Center, Shiraz University of Medical Sciences, Research Tower, PO Box 71994-67985, Shiraz, Iran.
| | - Negar Azarpira
- Transplant Research Center, Shiraz University of Medical Sciences, Research Tower, PO Box 71994-67985, Shiraz, Iran.
| | - Mohammad Reza Fattahi
- Gastroenterohepatology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Saman Nikeghbalian
- Shiraz Transplant Center, Abu-Ali Sina Hospital, Shiraz University of Medical Sciences, Shiraz, Iran.,Transplant Research Center, Shiraz University of Medical Sciences, Research Tower, PO Box 71994-67985, Shiraz, Iran
| | - Seyed Ali Malek-Hosseini
- Shiraz Transplant Center, Abu-Ali Sina Hospital, Shiraz University of Medical Sciences, Shiraz, Iran.,Transplant Research Center, Shiraz University of Medical Sciences, Research Tower, PO Box 71994-67985, Shiraz, Iran
| | - Bita Geramizadeh
- Transplant Research Center, Shiraz University of Medical Sciences, Research Tower, PO Box 71994-67985, Shiraz, Iran
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Jung Y, Koo BK, Jang SY, Kim D, Lee H, Lee DH, Joo SK, Jung YJ, Park JH, Yoo T, Choi M, Lee MK, Kang SW, Chang MS, Kim W, Hwang GS. Association between circulating bile acid alterations and nonalcoholic steatohepatitis independent of obesity and diabetes mellitus. Liver Int 2021; 41:2892-2902. [PMID: 34358397 DOI: 10.1111/liv.15030] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/20/2021] [Revised: 06/22/2021] [Accepted: 07/27/2021] [Indexed: 12/12/2022]
Abstract
BACKGROUND AND AIMS Bile acid (BA) dysregulation is related to not only metabolic diseases but also nonalcoholic fatty liver disease (NAFLD). We investigated whether circulating BA levels are altered according to the histological severity of NAFLD independent of metabolic derangements. METHODS Global metabolic profiling and targeted BA analysis using sera collected from biopsy-proven no-NAFLD (n = 67), nonalcoholic fatty liver (NAFL) (n = 99), and nonalcoholic steatohepatitis (NASH, n = 75) subjects were performed sequentially. Circulating metabolome analysis integrated with the hepatic transcriptome was performed to elucidate the mechanistic basis of altered circulating BA profiles after stratification by obesity (body mass index ≤ 25 kg/m2 ). Circulating BA alterations were also validated in an independent validation cohort (29 no-NAFLD, 70 NAFL and 37 NASH). RESULTS Global profiling analysis showed that BA was the metabolite significantly altered in NASH compared to NAFL. Targeted BA analysis demonstrated that glyco-/tauro-conjugated primary BAs were commonly increased in nonobese and obese NASH, while unconjugated primary BAs increased only in nonobese NASH. These characteristic primary BA level changes were maintained even after stratification according to diabetes status and were replicated in the independent validation cohort. Compared to nonobese NAFL patients, nonobese NASH patients exhibited upregulated hepatic expression of CYP8B1. CONCLUSIONS BA metabolism is dysregulated as the histological severity of NAFLD worsens, independent of obesity and diabetes status; dysregulation is more prominent in nonobese NAFLD patients. Metabolome-driven omics approach provides new insight into our understanding of altered BA metabolism associated with individual phenotypes of NAFLD.
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Affiliation(s)
- Youngae Jung
- Integrated Metabolomics Research Group, Western Seoul Center, Korea Basic Science Institute, Seoul, Republic of Korea.,Department of Life Science, Ewha Womans University, Seoul, Republic of Korea
| | - Bo Kyung Koo
- Division of Endocrinology, Department of Internal Medicine, Seoul National University College of Medicine, Seoul Metropolitan Government Boramae Medical Center, Seoul, Republic of Korea
| | - Seo Young Jang
- Integrated Metabolomics Research Group, Western Seoul Center, Korea Basic Science Institute, Seoul, Republic of Korea.,Department of Chemistry & Nanoscience, Ewha Womans University, Seoul, Republic of Korea
| | - Dain Kim
- Integrated Metabolomics Research Group, Western Seoul Center, Korea Basic Science Institute, Seoul, Republic of Korea.,Department of Life Science, Ewha Womans University, Seoul, Republic of Korea
| | - Heeyeon Lee
- Integrated Metabolomics Research Group, Western Seoul Center, Korea Basic Science Institute, Seoul, Republic of Korea.,Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul, Republic of Korea
| | - Dong Hyeon Lee
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Seoul National University College of Medicine, Seoul Metropolitan Government Boramae Medical Center, Seoul, Republic of Korea
| | - Sae Kyung Joo
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Seoul National University College of Medicine, Seoul Metropolitan Government Boramae Medical Center, Seoul, Republic of Korea
| | - Yong Jin Jung
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Seoul National University College of Medicine, Seoul Metropolitan Government Boramae Medical Center, Seoul, Republic of Korea
| | - Jeong Hwan Park
- Department of Pathology, Seoul National University College of Medicine, Seoul Metropolitan Government Boramae Medical Center, Seoul, Republic of Korea
| | - Taekyeong Yoo
- Department of Biochemical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Murim Choi
- Department of Biochemical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Min Kyung Lee
- Integrated Metabolomics Research Group, Western Seoul Center, Korea Basic Science Institute, Seoul, Republic of Korea.,Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul, Republic of Korea
| | - Sang Won Kang
- Department of Life Science, Ewha Womans University, Seoul, Republic of Korea
| | - Mee Soo Chang
- Department of Pathology, Seoul National University College of Medicine, Seoul Metropolitan Government Boramae Medical Center, Seoul, Republic of Korea
| | - Won Kim
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Seoul National University College of Medicine, Seoul Metropolitan Government Boramae Medical Center, Seoul, Republic of Korea
| | - Geum-Sook Hwang
- Integrated Metabolomics Research Group, Western Seoul Center, Korea Basic Science Institute, Seoul, Republic of Korea.,Department of Chemistry & Nanoscience, Ewha Womans University, Seoul, Republic of Korea
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36
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Schwartz S, Lucas J, DeLegge MH. Non-alcoholic Steatohepatitis: From Pathophysiology to Clinical Practice. TOUCHREVIEWS IN ENDOCRINOLOGY 2021; 17:112-120. [PMID: 35118457 PMCID: PMC8676103 DOI: 10.17925/ee.2021.17.2.112] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/02/2020] [Accepted: 02/01/2021] [Indexed: 11/24/2022]
Abstract
Non-alcoholic steatohepatitis (NASH) is becoming a global disease with significant associated comorbidities. To date, there are no commercialized drugs to treat NASH, outside of India; however, there is an abundance of new molecular entities which are in clinical development, some in phase III trials. Many of these trials have created an especially heavy demand for USA-based subjects. Hepatologists currently play a major role in the diagnosis, treatment and clinical-trial enrolment of patients with NASH. However, NASH has a strong metabolic component, with patients often carrying comorbid diseases, such as type 2 diabetes mellitus, obesity, hyperlipidaemia, hypothyroidism and sex steroid disorders. The primary care physician, internist and endocrinologist stand at a pivotal position in the NASH healthcare delivery system, as many of the diseases they commonly encounter are associated with a higher risk of developing NASH. Specialty society practice guidelines are evolving regarding the identification and care of patients with NASH. This review of the literature, and assessment of IQVIA's proprietary patient claims database of diagnosis codes, patient encounters and treatments, substantiates the importance of the primary care provider and endocrinologist in the clinical care and clinical research of patients with NASH.
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Slieker RC, Donnelly LA, Fitipaldi H, Bouland GA, Giordano GN, Åkerlund M, Gerl MJ, Ahlqvist E, Ali A, Dragan I, Elders P, Festa A, Hansen MK, van der Heijden AA, Mansour Aly D, Kim M, Kuznetsov D, Mehl F, Klose C, Simons K, Pavo I, Pullen TJ, Suvitaival T, Wretlind A, Rossing P, Lyssenko V, Legido Quigley C, Groop L, Thorens B, Franks PW, Ibberson M, Rutter GA, Beulens JWJ, 't Hart LM, Pearson ER. Distinct Molecular Signatures of Clinical Clusters in People With Type 2 Diabetes: An IMI-RHAPSODY Study. Diabetes 2021; 70:2683-2693. [PMID: 34376475 PMCID: PMC8564413 DOI: 10.2337/db20-1281] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/22/2020] [Accepted: 08/01/2021] [Indexed: 11/23/2022]
Abstract
Type 2 diabetes is a multifactorial disease with multiple underlying aetiologies. To address this heterogeneity, investigators of a previous study clustered people with diabetes according to five diabetes subtypes. The aim of the current study is to investigate the etiology of these clusters by comparing their molecular signatures. In three independent cohorts, in total 15,940 individuals were clustered based on five clinical characteristics. In a subset, genetic (N = 12,828), metabolomic (N = 2,945), lipidomic (N = 2,593), and proteomic (N = 1,170) data were obtained in plasma. For each data type, each cluster was compared with the other four clusters as the reference. The insulin-resistant cluster showed the most distinct molecular signature, with higher branched-chain amino acid, diacylglycerol, and triacylglycerol levels and aberrant protein levels in plasma were enriched for proteins in the intracellular PI3K/Akt pathway. The obese cluster showed higher levels of cytokines. The mild diabetes cluster with high HDL showed the most beneficial molecular profile with effects opposite of those seen in the insulin-resistant cluster. This study shows that clustering people with type 2 diabetes can identify underlying molecular mechanisms related to pancreatic islets, liver, and adipose tissue metabolism. This provides novel biological insights into the diverse aetiological processes that would not be evident when type 2 diabetes is viewed as a homogeneous disease.
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Affiliation(s)
- Roderick C Slieker
- Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden, the Netherlands
- Department of Epidemiology and Data Science, Amsterdam Public Health Institute, Amsterdam UMC, location VUmc, Amsterdam, the Netherlands
| | - Louise A Donnelly
- Population Health & Genomics, School of Medicine, University of Dundee, Dundee, U.K
| | - Hugo Fitipaldi
- Genetic and Molecular Epidemiology Unit, Lund University Diabetes Centre, Department of Clinical Sciences, Clinical Research Centre, Lund University, SUS, Malmö, Sweden
| | - Gerard A Bouland
- Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden, the Netherlands
| | - Giuseppe N Giordano
- Genetic and Molecular Epidemiology Unit, Lund University Diabetes Centre, Department of Clinical Sciences, Clinical Research Centre, Lund University, SUS, Malmö, Sweden
| | - Mikael Åkerlund
- Genetic and Molecular Epidemiology Unit, Lund University Diabetes Centre, Department of Clinical Sciences, Clinical Research Centre, Lund University, SUS, Malmö, Sweden
| | | | - Emma Ahlqvist
- Genetic and Molecular Epidemiology Unit, Lund University Diabetes Centre, Department of Clinical Sciences, Clinical Research Centre, Lund University, SUS, Malmö, Sweden
| | - Ashfaq Ali
- Steno Diabetes Center Copenhagen, Gentofte, Denmark
| | - Iulian Dragan
- Vital-IT Group, SIB Swiss Institute of Bioinformatics, Lausanne, Switzerland
| | - Petra Elders
- Department of General Practice and Elderly Care Medicine, Amsterdam Public Health Research Institute, Amsterdam UMC, location VUmc, Amsterdam, the Netherlands
| | - Andreas Festa
- Eli Lilly Regional Operations GmbH, Vienna, Austria
- 1st Medical Department, LK Stockerau, Niederösterreich, Austria
| | - Michael K Hansen
- Cardiovascular and Metabolic Disease Research, Janssen Research & Development, Spring House, PA
| | - Amber A van der Heijden
- Department of General Practice and Elderly Care Medicine, Amsterdam Public Health Research Institute, Amsterdam UMC, location VUmc, Amsterdam, the Netherlands
| | - Dina Mansour Aly
- Genetic and Molecular Epidemiology Unit, Lund University Diabetes Centre, Department of Clinical Sciences, Clinical Research Centre, Lund University, SUS, Malmö, Sweden
| | - Min Kim
- Steno Diabetes Center Copenhagen, Gentofte, Denmark
- Institute of Pharmaceutical Science, Faculty of Life Sciences and Medicines, King's College London, London, U.K
| | - Dmitry Kuznetsov
- Vital-IT Group, SIB Swiss Institute of Bioinformatics, Lausanne, Switzerland
| | - Florence Mehl
- Vital-IT Group, SIB Swiss Institute of Bioinformatics, Lausanne, Switzerland
| | | | | | - Imre Pavo
- Eli Lilly Regional Operations GmbH, Vienna, Austria
| | - Timothy J Pullen
- Department of Diabetes, Guy's Campus, King's College London, London, U.K
- Section of Cell Biology and Functional Genomics, Division of Diabetes, Endocrinology and Metabolism, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, U.K
| | | | | | - Peter Rossing
- Steno Diabetes Center Copenhagen, Gentofte, Denmark
- Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
| | - Valeriya Lyssenko
- Department of Clinical Science, Center for Diabetes Research, University of Bergen, Bergen, Norway
- Genomics, Diabetes and Endocrinology Unit, Department of Clinical Sciences Malmö, Lund University Diabetes Centre, Skåne University Hospital, Malmö, Sweden
| | - Cristina Legido Quigley
- Steno Diabetes Center Copenhagen, Gentofte, Denmark
- Cardiovascular and Metabolic Disease Research, Janssen Research & Development, Spring House, PA
| | - Leif Groop
- Genetic and Molecular Epidemiology Unit, Lund University Diabetes Centre, Department of Clinical Sciences, Clinical Research Centre, Lund University, SUS, Malmö, Sweden
- Finnish Institute of Molecular Medicine, Helsinki University, Helsinki, Finland
| | - Bernard Thorens
- Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland
| | - Paul W Franks
- Genetic and Molecular Epidemiology Unit, Lund University Diabetes Centre, Department of Clinical Sciences, Clinical Research Centre, Lund University, SUS, Malmö, Sweden
- Department of Nutrition, Harvard School of Public Health, Boston, MA
| | - Mark Ibberson
- Vital-IT Group, SIB Swiss Institute of Bioinformatics, Lausanne, Switzerland
| | - Guy A Rutter
- Department of Diabetes, Guy's Campus, King's College London, London, U.K
- Lee Kong Chian School of Medicine, Nan Yang Technological University, Singapore
| | - Joline W J Beulens
- Department of Epidemiology and Data Science, Amsterdam Public Health Institute, Amsterdam UMC, location VUmc, Amsterdam, the Netherlands
- Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, the Netherlands
| | - Leen M 't Hart
- Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden, the Netherlands
- Department of Epidemiology and Data Science, Amsterdam Public Health Institute, Amsterdam UMC, location VUmc, Amsterdam, the Netherlands
- Molecular Epidemiology, Department of Biomedical Data Sciences, Leiden University Medical Center, Leiden, the Netherlands
| | - Ewan R Pearson
- Population Health & Genomics, School of Medicine, University of Dundee, Dundee, U.K.
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Si J, Lee G, You HJ, Joo SK, Lee DH, Ku BJ, Park S, Kim W, Ko G. Gut microbiome signatures distinguish type 2 diabetes mellitus from non-alcoholic fatty liver disease. Comput Struct Biotechnol J 2021; 19:5920-5930. [PMID: 34849196 PMCID: PMC8591343 DOI: 10.1016/j.csbj.2021.10.032] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2021] [Revised: 10/22/2021] [Accepted: 10/26/2021] [Indexed: 02/08/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is closely associated with type 2 diabetes mellitus (T2D), and these two metabolic diseases demonstrate bidirectional influences. The identification of microbiome profiles that are specific to liver injury or impaired glucose metabolism may assist understanding of the role of the gut microbiota in the relationship between NAFLD and T2D. Here, we studied a biopsy-proven Asian NAFLD cohort (n = 329; 187 participants with NAFLD, 101 with NAFLD and T2D, and 41 with neither) and identified Enterobacter, Romboutsia, and Clostridium sensu stricto as the principal taxa associated with the severity of NAFLD and T2D, whereas Ruminococcus and Megamonas were specific to NAFLD. In particular, the taxa that were associated with both severe liver pathology and T2D were also significantly associated with markers of diabetes, such as fasting blood glucose and Hb1Ac. Enterotype analysis demonstrated that participants with NAFLD had a significantly higher proportion of Bacteroides and a lower proportion of Ruminococcus than a Korean healthy twin cohort (n = 756). However, T2D could not be clearly distinguished from NAFLD. Analysis of an independent T2D cohort (n = 185) permitted us to validate the T2D-specific bacterial signature identified in the NAFLD cohort. Functional inference analysis revealed that endotoxin biosynthesis pathways were significantly enriched in participants with NAFLD and T2D, compared with those with NAFLD alone. These findings may assist with the development of effective therapeutic approaches for metabolic diseases that are associated with specific bacterial signatures.
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Key Words
- ALT, alanine aminotransferase
- BMI, body mass index
- Biomarker
- Enterotype
- FBS, fasting blood sugar
- FDR, false discovery rate
- FLI, fatty liver index
- Gut microbiome
- HbA1c, glycosylated hemoglobin
- LDL, low-density lipoprotein
- LPS, lipopolysaccharide
- MaAsLin2, microbiome multivariable association with linear models 2
- NAFL, non-alcoholic fatty liver
- NAFLD, non-alcoholic fatty liver disease
- NASH, non-alcoholic steatohepatitis
- NASH-CRN, non-alcoholic steatohepatitis clinical research network
- Non-alcoholic fatty liver disease (NAFLD)
- PICRUSt2, phylogenetic investigation of communities by reconstruction of unobserved states 2
- T2D, type 2 diabetes mellitus
- Type 2 diabetes mellitus
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Affiliation(s)
- Jiyeon Si
- Medical Science Research Institute, School of Medicine, Sungkyunkwan University (SKKU), Suwon 16419, Republic of Korea
| | - Giljae Lee
- Department of Environmental Health Sciences, Graduate School of Public Health, Seoul National University, Seoul 08826, Republic of Korea
| | - Hyun Ju You
- Department of Environmental Health Sciences, Graduate School of Public Health, Seoul National University, Seoul 08826, Republic of Korea
- Institute of Health and Environment, Seoul National University, Seoul 08826, Republic of Korea
| | - Sae Kyung Joo
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Seoul National University College of Medicine, Seoul Metropolitan Government Boramae Medical Center, Seoul 07061, Republic of Korea
| | - Dong Hyeon Lee
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Seoul National University College of Medicine, Seoul Metropolitan Government Boramae Medical Center, Seoul 07061, Republic of Korea
| | - Bon Jeong Ku
- Department of Internal Medicine, Chungnam National University School of Medicine, Daejeon 35015, Republic of Korea
| | - Seoyeon Park
- Department of Environmental Health Sciences, Graduate School of Public Health, Seoul National University, Seoul 08826, Republic of Korea
| | - Won Kim
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Seoul National University College of Medicine, Seoul Metropolitan Government Boramae Medical Center, Seoul 07061, Republic of Korea
| | - GwangPyo Ko
- Department of Environmental Health Sciences, Graduate School of Public Health, Seoul National University, Seoul 08826, Republic of Korea
- Center for Human and Environmental Microbiome, Institute of Health and Environment, Seoul National University, Seoul 08826, Republic of Korea
- KoBioLabs, Inc., Seoul 08826, Republic of Korea
- Bio-MAX/N-Bio, Seoul National University, Seoul 08826, Republic of Korea
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Moon JH, Kim W, Koo BK, Cho NH. Metabolic Dysfunction-Associated Fatty Liver Disease Predicts Long-term Mortality and Cardiovascular Disease. Gut Liver 2021; 16:433-442. [PMID: 34635626 PMCID: PMC9099391 DOI: 10.5009/gnl210167] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/12/2021] [Revised: 06/17/2021] [Accepted: 06/29/2021] [Indexed: 11/15/2022] Open
Abstract
Background/Aims We investigated the effect of metabolic dysfunction-associated fatty liver disease (MAFLD) on future mortality and cardiovascular disease (CVD) using a prospective community-based cohort study. Methods Individuals from two community-based cohorts who were 40 to 70 years old were prospectively followed for 16 years. MAFLD was defined as a high fatty liver index (FLI ≥60) plus one of the following conditions overweight/obesity (body mass index ≥23 kg/m2), type 2 diabetes mellitus, or ≥2 metabolic risk abnormalities. Nonalcoholic fatty liver disease (NAFLD) was defined as FLI ≥60 without any secondary cause of hepatic steatosis. Results Among 8,919 subjects (age 52.2±8.9 years, 47.7% of males), 1,509 (16.9%) had MAFLD. During the median follow-up of 15.7 years, MAFLD independently predicted overall mortality after adjustment for confounders (hazard ratio [HR], 1.33; 95% confidence interval [CI], 1.05 to 1.69) but NAFLD did not (HR, 1.20; 95% CI, 0.94 to 1.53). MAFLD also predicted CVD after adjustment for age, sex, and body mass index (HR, 1.35; 95% CI, 1.13 to 1.62), which lost its statistical significance by further adjustments. Stratified analysis indicated that metabolic dysfunction contributed to mortality (HR, 1.51; 95% CI, 1.21 to 1.89) and CVD (HR, 1.27; 95% CI, 1.02 to 1.59). Among metabolic dysfunctions used for defining MAFLD, type 2 diabetes mellitus in MAFLD increased the risk of both mortality (HR, 2.07; 95% CI, 1.52 to 2.81) and CVD (HR, 1.42; 95% CI, 1.09 to 1.85). Conclusions MAFLD independently increased overall mortality. Heterogeneity in mortality and CVD risk of subjects with MAFLD may be determined by the accompanying metabolic dysfunctions.
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Affiliation(s)
- Joon Ho Moon
- Department of Internal Medicine, Seoul National University College of Medicine, Seongnam, Korea.,Division of Endocrinology and Metabolism, Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Won Kim
- Department of Internal Medicine, Seoul National University College of Medicine, Seongnam, Korea.,Division of Gastroenterology and Hepatology, Department of Internal Medicine, SMG-SNU Boramae Medical Center, Seoul, Korea
| | - Bo Kyung Koo
- Department of Internal Medicine, Seoul National University College of Medicine, Seongnam, Korea.,Division of Endocrinology and Metabolism, Department of Internal Medicine, SMG-SNU Boramae Medical Center, Seoul, Korea
| | - Nam H Cho
- Department of Preventive Medicine, Ajou University School of Medicine, Suwon, Korea
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40
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Wang J, Conti DV, Bogumil D, Sheng X, Noureddin M, Wilkens LR, Le Marchand L, Rosen HR, Haiman CA, Setiawan VW. Association of Genetic Risk Score With NAFLD in An Ethnically Diverse Cohort. Hepatol Commun 2021; 5:1689-1703. [PMID: 34558842 PMCID: PMC8485887 DOI: 10.1002/hep4.1751] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/09/2021] [Accepted: 05/03/2021] [Indexed: 12/15/2022] Open
Abstract
Most genetic studies of nonalcoholic fatty liver disease (NAFLD) have been conducted in Whites. In this large and ethnically diverse cohort, we assessed the transportability of previously identified genetic variants for NAFLD, built a genetic risk score (GRS), and examined its association with NAFLD risk in multiple ethnic groups. Thirty previously identified genome-wide association studies (GWAS) variants (P < 5 × 10-8 ) and 17 other variants associated with NAFLD were examined in a nested case-control study of NAFLD (1,448 cases/8,444 controls) in this multi-ethnic cohort study. We then built a GRS using 11 independent single-nucleotide polymorphisms from these prior studies and examined its association with NAFLD by cirrhosis status across multiple ethnic groups. Of the 30 GWAS SNPs, 20 (67%) were replicated (P < 0.05) in the pooled multi-ethnic population. The highest percentage of replication was seen in Latinos (43%), followed by Japanese Americans (37%), Whites (17%), and Native Hawaiians and African Americans (≤10%). Several genetic variants, including those in PNPLA3 (patatin-like phospholipase domain containing 3), HSD17B13 (hydroxysteroid 17-beta dehydrogenase 13), TM6SF2 (transmembrane 6 superfamily member 2), GATAD2A (GATA zinc finger domain containing 2A), GCKR (glucokinase regulator), SUGP1 (SURP and G-patch domain containing 1), MBOAT7 (membrane bound O-acyltransferase domain containing 7), TRIB1 (tribbles pseudokinase 1), SAMM50 (sorting and assembly machinery component), and ERLIN1 (ER lipid raft associated 1)-CHUK (component of inhibitor of nuclear factor kappa B kinase complex)-CWF19L1 (CWF19 like cell cycle control factor 1) gene cluster, were replicated in at least two ethnic groups. An 11-SNP weighted GRS was associated with NAFLD risk in the multi-ethnic population (odds ratio [OR] per SD increase = 1.41; 95% confidence interval [CI] = 1.32-1.50), as well as in each ethnic group (OR ranged from 1.30 in African Americans to 1.52 in Latinos). The GRS-NAFLD association was stronger for NAFLD with cirrhosis (OR = 1.67; 95% CI = 1.46-1.92) compared to NAFLD without cirrhosis (OR = 1.37; 95% CI = 1.28-1.46) (P heterogeneity = 0.003). Conclusion: In this ethnically diverse cohort, we replicated several key genetic variants for NAFLD and showed the utility of GRS based on the risk alleles for NAFLD risk stratification in multiple ethnic groups.
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Affiliation(s)
- Jun Wang
- Department of Preventive MedicineKeck School of Medicine of University of Southern CaliforniaLos AngelesCAUSA
| | - David V. Conti
- Department of Preventive MedicineKeck School of Medicine of University of Southern CaliforniaLos AngelesCAUSA
- Center for Genetic EpidemiologyKeck School of MedicineUniversity of Southern CaliforniaLos AngelesCAUSA
- Norris Comprehensive Cancer CenterKeck School of Medicine of University of Southern CaliforniaLos AngelesCAUSA
| | - David Bogumil
- Department of Preventive MedicineKeck School of Medicine of University of Southern CaliforniaLos AngelesCAUSA
| | - Xin Sheng
- Department of Preventive MedicineKeck School of Medicine of University of Southern CaliforniaLos AngelesCAUSA
| | - Mazen Noureddin
- Division of Gastroenterology and HepatologyDepartment of MedicineCedars‐Sinai Medical CenterLos AngelesCAUSA
| | - Lynne R. Wilkens
- Epidemiology ProgramUniversity of Hawaii Cancer CenterHonoluluHIUSA
| | - Loic Le Marchand
- Epidemiology ProgramUniversity of Hawaii Cancer CenterHonoluluHIUSA
| | - Hugo R. Rosen
- Department of MedicineKeck School of Medicine of University of Southern CaliforniaLos AngelesCAUSA
| | - Christopher A. Haiman
- Department of Preventive MedicineKeck School of Medicine of University of Southern CaliforniaLos AngelesCAUSA
- Center for Genetic EpidemiologyKeck School of MedicineUniversity of Southern CaliforniaLos AngelesCAUSA
- Norris Comprehensive Cancer CenterKeck School of Medicine of University of Southern CaliforniaLos AngelesCAUSA
| | - Veronica Wendy Setiawan
- Department of Preventive MedicineKeck School of Medicine of University of Southern CaliforniaLos AngelesCAUSA
- Center for Genetic EpidemiologyKeck School of MedicineUniversity of Southern CaliforniaLos AngelesCAUSA
- Norris Comprehensive Cancer CenterKeck School of Medicine of University of Southern CaliforniaLos AngelesCAUSA
- Department of MedicineKeck School of Medicine of University of Southern CaliforniaLos AngelesCAUSA
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Meroni M, Longo M, Tria G, Dongiovanni P. Genetics Is of the Essence to Face NAFLD. Biomedicines 2021; 9:1359. [PMID: 34680476 PMCID: PMC8533437 DOI: 10.3390/biomedicines9101359] [Citation(s) in RCA: 40] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2021] [Accepted: 09/27/2021] [Indexed: 02/07/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is the commonest cause of chronic liver disease worldwide. It is closely related to obesity, insulin resistance (IR) and dyslipidemia so much so it is considered the hepatic manifestation of the Metabolic Syndrome. The NAFLD spectrum extends from simple steatosis to nonalcoholic steatohepatitis (NASH), a clinical condition which may progress up to fibrosis, cirrhosis and hepatocellular carcinoma (HCC). NAFLD is a complex disease whose pathogenesis is shaped by both environmental and genetic factors. In the last two decades, several heritable modifications in genes influencing hepatic lipid remodeling, and mitochondrial oxidative status have been emerged as predictors of progressive hepatic damage. Among them, the patatin-like phospholipase domain-containing 3 (PNPLA3) p.I148M, the Transmembrane 6 superfamily member 2 (TM6SF2) p.E167K and the rs641738 membrane bound-o-acyltransferase domain-containing 7 (MBOAT7) polymorphisms are considered the most robust modifiers of NAFLD. However, a forefront frontier in the study of NAFLD heritability is to postulate score-based strategy, building polygenic risk scores (PRS), which aggregate the most relevant genetic determinants of NAFLD and biochemical parameters, with the purpose to foresee patients with greater risk of severe NAFLD, guaranteeing the most highly predictive value, the best diagnostic accuracy and the more precise individualized therapy.
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Affiliation(s)
- Marica Meroni
- General Medicine and Metabolic Diseases, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Pad. Granelli, Via F Sforza 35, 20122 Milan, Italy; (M.M.); (M.L.); (G.T.)
| | - Miriam Longo
- General Medicine and Metabolic Diseases, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Pad. Granelli, Via F Sforza 35, 20122 Milan, Italy; (M.M.); (M.L.); (G.T.)
- Department of Clinical Sciences and Community Health, Università Degli Studi di Milano, 20122 Milano, Italy
| | - Giada Tria
- General Medicine and Metabolic Diseases, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Pad. Granelli, Via F Sforza 35, 20122 Milan, Italy; (M.M.); (M.L.); (G.T.)
| | - Paola Dongiovanni
- General Medicine and Metabolic Diseases, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Pad. Granelli, Via F Sforza 35, 20122 Milan, Italy; (M.M.); (M.L.); (G.T.)
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Yoo T, Joo SK, Kim HJ, Kim HY, Sim H, Lee J, Kim HH, Jung S, Lee Y, Jamialahmadi O, Romeo S, Jeong WI, Hwang GS, Kang KW, Kim JW, Kim W, Choi M. Disease-specific eQTL screening reveals an anti-fibrotic effect of AGXT2 in non-alcoholic fatty liver disease. J Hepatol 2021; 75:514-523. [PMID: 33892010 DOI: 10.1016/j.jhep.2021.04.011] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/24/2020] [Revised: 03/22/2021] [Accepted: 04/07/2021] [Indexed: 12/19/2022]
Abstract
BACKGROUND & AIMS Non-alcoholic fatty liver disease (NAFLD) poses an increasing clinical burden. Genome-wide association studies have revealed a limited contribution of genomic variants to the disease, requiring alternative but robust approaches to identify disease-associated variants and genes. We carried out a disease-specific expression quantitative trait loci (eQTL) screen to identify novel genetic factors that specifically act on NAFLD progression on the basis of genotype. METHODS We recruited 125 Korean patients (83 with biopsy-proven NAFLD and 42 without NAFLD) and performed eQTL analyses using 21,272 transcripts and 3,234,941 genotyped and imputed single nucleotide polymorphisms. We then selected eQTLs that were detected only in the NAFLD group, but not in the control group (i.e., NAFLD-eQTLs). An additional cohort of 162 Korean individuals with NAFLD was used for replication. The function of the selected eQTL toward NAFLD development was validated using HepG2, primary hepatocytes and NAFLD mouse models. RESULTS The NAFLD-specific eQTL screening yielded 242 loci. Among them, AGXT2, encoding alanine-glyoxylate aminotransferase 2, displayed decreased expression in patients with NAFLD homozygous for the non-reference allele of rs2291702, compared to no-NAFLD individuals with the same genotype (p = 4.79 × 10-6). This change was replicated in an additional 162 individuals, yielding a combined p value of 8.05 × 10-8 from a total of 245 patients with NAFLD and 42 controls. Knockdown of AGXT2 induced palmitate-overloaded hepatocyte death by increasing endoplasmic reticulum stress, and exacerbated NAFLD diet-induced liver fibrosis in mice, while overexpression of AGXT2 attenuated liver fibrosis and steatosis. CONCLUSIONS We identified a new molecular role for AGXT2 in NAFLD. Our overall approach will serve as an efficient tool for uncovering novel genetic factors that contribute to liver steatosis and fibrosis in patients with NAFLD. LAY SUMMARY Elucidating causal genes for non-alcoholic fatty liver disease (NAFLD) has been challenging due to limited tissue availability and the polygenic nature of the disease. Using liver and blood samples from 125 Korean individuals (83 with NAFLD and 42 without NAFLD), we devised a new analytic method to identify causal genes. Among the candidates, we found that AGXT2-rs2291702 protects against liver fibrosis in a genotype-dependent manner with the potential for therapeutic interventions. Our approach enables the discovery of causal genes that act on the basis of genotype.
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Affiliation(s)
- Taekyeong Yoo
- Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Sae Kyung Joo
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul Metropolitan Government Boramae Medical Center, Seoul, Republic of Korea
| | - Hyo Jung Kim
- Department of Biochemistry and Molecular Biology, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Hyun Young Kim
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Republic of Korea
| | - Hyungtai Sim
- Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Jieun Lee
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul Metropolitan Government Boramae Medical Center, Seoul, Republic of Korea
| | - Hee-Hoon Kim
- Laboratory of Liver Research, Graduate School of Medical Science and Engineering, KAIST, Daejeon, Republic of Korea
| | - Sunhee Jung
- Integrated Metabolomics Research Group, Western Seoul Center, Korea Basic Science Institute, Seoul, Republic of Korea
| | - Youngha Lee
- Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Oveis Jamialahmadi
- Salhgrenska Academy, Institute of Medicine, Department of Molecular and Clinical Medicine, University of Gothenburg, Sweden
| | - Stefano Romeo
- Salhgrenska Academy, Institute of Medicine, Department of Molecular and Clinical Medicine, University of Gothenburg, Sweden; Sahlgrenska University Hospital, Cardiology Department, Sweden; Department of Medical and Clinical Science, Clinical Nutrition Unit, University Magna Graecia, Catanzaro, Italy
| | - Won-Il Jeong
- Laboratory of Liver Research, Graduate School of Medical Science and Engineering, KAIST, Daejeon, Republic of Korea
| | - Geum-Sook Hwang
- Integrated Metabolomics Research Group, Western Seoul Center, Korea Basic Science Institute, Seoul, Republic of Korea; Department of Chemistry & Nanoscience, Ewha Womans University, Seoul, Republic of Korea
| | - Keon Wook Kang
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Republic of Korea
| | - Jae Woo Kim
- Department of Biochemistry and Molecular Biology, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Won Kim
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul Metropolitan Government Boramae Medical Center, Seoul, Republic of Korea.
| | - Murim Choi
- Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea.
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Mansoor S, Maheshwari A, Di Guglielmo M, Furuya K, Wang M, Crowgey E, Molle-Rios Z, He Z. The PNPLA3 rs738409 Variant but not MBOAT7 rs641738 is a Risk Factor for Nonalcoholic Fatty Liver Disease in Obese U.S. Children of Hispanic Ethnicity. Pediatr Gastroenterol Hepatol Nutr 2021; 24:455-469. [PMID: 34557398 PMCID: PMC8443857 DOI: 10.5223/pghn.2021.24.5.455] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Revised: 06/25/2021] [Accepted: 07/17/2021] [Indexed: 12/18/2022] Open
Abstract
PURPOSE The rs641738 C>T in membrane-bound O-acyltransferase domain-containing protein 7 (MBOAT7) is implicated, along with the rs738409 C>G polymorphism in patatin-like phospholipase domain-containing protein 3 (PNPLA3), in nonalcoholic fatty liver disease (NAFLD). The association of these polymorphisms and NAFLD are investigated in Hispanic children with obesity. METHODS Obese children with and without NAFLD were enrolled at a pediatric tertiary care health system and genotyped for MBOAT7 rs641738 C>T and PNPLA3 rs738409 C>G. NAFLD was characterized by the ultrasonographic presence of hepatic steatosis along with persistently elevated liver enzymes. Genetic variants and demographic and biochemical data were analyzed for the effects on NAFLD. RESULTS Among 126 enrolled subjects, 84 in the case group had NAFLD and 42 in the control group did not. The two groups had similar demographic distribution. NAFLD was associated with abnormal liver enzymes and elevated triglycerides and cholesterol (p<0.05). Children with NAFLD had higher percentage of PNPLA3 GG genotype at 70.2% versus 31.0% in non-NAFLD, and lower MBOAT7 TT genotype at 4.8% versus 16.7% in non-NAFLD (p<0.05). PNPLA3 rs738409 C>G had an additive effect in NAFLD; however, MBOAT7 rs641738 C>T had no effects alone or synergistically with PNPLA3 polymorphism. NAFLD risk increased 3.7-fold in subjects carrying PNPLA3 GG genotype and decreased in MBOAT7 TT genotype. CONCLUSION In Hispanic children with obesity, PNPLA3 rs738409 C>G polymorphism increased the risk for NAFLD. The role of MBOAT7 rs641738 variant in NAFLD is less evident.
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Affiliation(s)
- Sana Mansoor
- Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Nemours/Alfred I. duPont Hospital for Children, Wilmington, DE, USA
| | - Anshu Maheshwari
- Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Nemours/Alfred I. duPont Hospital for Children, Wilmington, DE, USA
| | - Matthew Di Guglielmo
- Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Nemours/Alfred I. duPont Hospital for Children, Wilmington, DE, USA.,Department of Pediatrics, Sidney Kimmel Medical College Thomas Jefferson University, Philadelphia, PA, USA
| | - Katryn Furuya
- Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Nemours/Alfred I. duPont Hospital for Children, Wilmington, DE, USA
| | - Makala Wang
- Department of Biomedical Research, Nemours/Alfred I. duPont Hospital for Children, Wilmington, DE, USA
| | - Erin Crowgey
- Department of Biomedical Research, Nemours/Alfred I. duPont Hospital for Children, Wilmington, DE, USA.,Department of Pediatrics, Sidney Kimmel Medical College Thomas Jefferson University, Philadelphia, PA, USA
| | - Zarela Molle-Rios
- Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Nemours/Alfred I. duPont Hospital for Children, Wilmington, DE, USA.,Department of Pediatrics, Sidney Kimmel Medical College Thomas Jefferson University, Philadelphia, PA, USA
| | - Zhaoping He
- Department of Biomedical Research, Nemours/Alfred I. duPont Hospital for Children, Wilmington, DE, USA.,Department of Pediatrics, Sidney Kimmel Medical College Thomas Jefferson University, Philadelphia, PA, USA
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Paternostro R, Staufer K, Traussnigg S, Stättermayer AF, Halilbasic E, Keritam O, Meyer EL, Stift J, Wrba F, Sipos B, Canbay A, Schlattjan M, Aigner E, Datz C, Stickel F, Schafmayer C, Hampe J, Buch S, Prager G, Munda P, Mandorfer M, Ferenci P, Trauner M. Combined effects of PNPLA3, TM6SF2 and HSD17B13 variants on severity of biopsy-proven non-alcoholic fatty liver disease. Hepatol Int 2021; 15:922-933. [PMID: 34076851 PMCID: PMC8382644 DOI: 10.1007/s12072-021-10200-y] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2021] [Accepted: 04/24/2021] [Indexed: 12/13/2022]
Abstract
OBJECTIVE Several single-nucleotide polymorphisms have been identified to be disadvantageous or protective in regard to disease severity in patients with non-alcoholic fatty liver disease (NAFLD). However, it is unclear, whether including genetic risk factor(s) either alone or combined into risk stratification algorithms for NAFLD actually provides incremental benefit over clinical risk factors. DESIGN Patients with biopsy-proven NAFLD were genotyped for the PNPLA3-rs738409(minor allele:G), TM6SF2-rs58542926(minor allele:T) and HSD17B13- rs72613567 (minor allele:TA) variants. The NAFLD activity score (NAS) and fibrosis stage (F0-F4) were used to grade and stage all liver biopsy samples. Patients from seven centers throughout Central Europe were considered for the study. RESULTS 703 patients were included: NAS ≥ 5:173(24.6%); Fibrosis: F3-4:81(11.5%). PNPLA3 G/G genotype was associated with a NAS ≥ 5(aOR 2.23, p = 0.007) and advanced fibrosis (aOR-3.48, p < 0.001).TM6SF2 T/- was associated with advanced fibrosis (aOR 1.99, p = 0.023). HSD17B13 TA/- was associated with a lower probability of NAS ≥ 5(TA/T: aOR 0.65, p = 0.041, TA/TA: aOR 0.40, p = 0.033). Regarding the predictive capability for NAS ≥ 5, well-known risk factors (age, sex, BMI, diabetes, and ALT; baseline model) had an AUC of 0.758, Addition of PNPLA3(AUC 0.766), HSB17B13(AUC 0.766), and their combination(AUC 0.775), but not of TM6SF2(AUC 0.762), resulted in a higher diagnostic accuracy of the model. Addition of genetic markers for the prediction of advanced fibrosis (baseline model: age, sex, BMI, diabetes: AUC 0.777) resulted in a higher AUC if PNPLA3(AUC 0.789), and TM6SF2(AUC 0.786) but not if HSD17B13(0.777) were added. CONCLUSION In biopsy-proven NAFLD, PNPLA3 G/-, TM6SF2 T/- and HSD17B13 TA/- carriage are associated with severity of NAFLD. Incorporating these genetic risk factors into risk stratification models might improve their predictive accuracy for severity of NAFLD and/or advanced fibrosis on liver biopsy.
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Affiliation(s)
- Rafael Paternostro
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria
| | - Katharina Staufer
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria
- Department of Visceral Surgery and Medicine, Inselspital, University Hospital Bern, Bern, Switzerland
| | - Stefan Traussnigg
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria
| | - Albert-Friedrich Stättermayer
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria
| | - Emina Halilbasic
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria
| | - Omar Keritam
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria
| | - Elias L Meyer
- Center for Medical Statistics, Informatics and Intelligent Systems, Medical University of Vienna, Vienna, Austria
| | - Judith Stift
- Department of Pathology, Medical University of Vienna, Vienna, Austria
| | - Fritz Wrba
- Department of Pathology, Medical University of Vienna, Vienna, Austria
| | - Bence Sipos
- Department of Pathology, Eberhard Karls University Tübingen, Tübingen, Germany
| | - Ali Canbay
- Department of Medicine, Ruhr-Universität Bochum, Bochum, Germany
| | - Martin Schlattjan
- Department of Gastroenterology and Hepatology, University Hospital Essen, Essen, Germany
| | - Elmar Aigner
- First Department of Medicine, Paracelsus Medical University, Salzburg, Austria
| | - Christian Datz
- Department of Internal Medicine, Oberndorf Hospital, Oberndorf, Austria
| | - Felix Stickel
- Department of Gastroenterology and Hepatology, University Hospital of Zurich, Zürich, Switzerland
| | - Clemens Schafmayer
- Department of General Surgery, University Medicine Rostock, Rostock, Germany
| | - Jochen Hampe
- Medical Department 1, University Hospital Dresden, Technische Universität Dresden, Dresden, Germany
| | - Stephan Buch
- Medical Department 1, University Hospital Dresden, Technische Universität Dresden, Dresden, Germany
| | - Gerhard Prager
- Division of General Surgery, Department of Surgery, Medical University of Vienna, Vienna, Austria
| | - Petra Munda
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria
| | - Mattias Mandorfer
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria
| | - Peter Ferenci
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria
| | - Michael Trauner
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria.
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Bence KK, Birnbaum MJ. Metabolic drivers of non-alcoholic fatty liver disease. Mol Metab 2021; 50:101143. [PMID: 33346069 PMCID: PMC8324696 DOI: 10.1016/j.molmet.2020.101143] [Citation(s) in RCA: 125] [Impact Index Per Article: 31.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/26/2020] [Revised: 12/02/2020] [Accepted: 12/11/2020] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND The incidence of non-alcoholic fatty liver disease (NAFLD) is rapidly increasing worldwide parallel to the global obesity epidemic. NAFLD encompasses a range of liver pathologies and most often originates from metabolically driven accumulation of fat in the liver, or non-alcoholic fatty liver (NAFL). In a subset of NAFL patients, the disease can progress to non-alcoholic steatohepatitis (NASH), which is a more severe form of liver disease characterized by hepatocyte injury, inflammation, and fibrosis. Significant progress has been made over the past decade in our understanding of NASH pathogenesis, but gaps remain in our mechanistic knowledge of the precise metabolic triggers for disease worsening. SCOPE OF REVIEW The transition from NAFL to NASH likely involves a complex constellation of multiple factors intrinsic and extrinsic to the liver. This review focuses on early metabolic events in the establishment of NAFL and initial stages of NASH. We discuss the association of NAFL with obesity as well as the role of adipose tissue in disease progression and highlight early metabolic drivers implicated in the pathological transition from hepatic fat accumulation to steatohepatitis. MAJOR CONCLUSIONS The close association of NAFL with features of metabolic syndrome highlight plausible mechanistic roles for adipose tissue health and the release of lipotoxic lipids, hepatic de novo lipogenesis (DNL), and disruption of the intestinal barrier in not only the initial establishment of hepatic steatosis, but also in mediating disease progression. Human genetic variants linked to NASH risk to date are heavily biased toward genes involved in the regulation of lipid metabolism, providing compelling support for the hypothesis that NASH is fundamentally a metabolic disease.
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Affiliation(s)
- Kendra K Bence
- Internal Medicine Research Unit, Pfizer Worldwide Research, Development, and Medical, Cambridge, MA, USA.
| | - Morris J Birnbaum
- Internal Medicine Research Unit, Pfizer Worldwide Research, Development, and Medical, Cambridge, MA, USA
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Diagnosis and management of secondary causes of steatohepatitis. J Hepatol 2021; 74:1455-1471. [PMID: 33577920 DOI: 10.1016/j.jhep.2021.01.045] [Citation(s) in RCA: 63] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/13/2020] [Revised: 01/09/2021] [Accepted: 01/25/2021] [Indexed: 02/06/2023]
Abstract
The term non-alcoholic fatty liver disease (NAFLD) was originally coined to describe hepatic fat deposition as part of the metabolic syndrome. However, a variety of rare hereditary liver and metabolic diseases, intestinal diseases, endocrine disorders and drugs may underlie, mimic, or aggravate NAFLD. In contrast to primary NAFLD, therapeutic interventions are available for many secondary causes of NAFLD. Accordingly, secondary causes of fatty liver disease should be considered during the diagnostic workup of patients with fatty liver disease, and treatment of the underlying disease should be started to halt disease progression. Common genetic variants in several genes involved in lipid handling and metabolism modulate the risk of progression from steatosis to fibrosis, cirrhosis and hepatocellular carcinoma development in NAFLD, alcohol-related liver disease and viral hepatitis. Hence, we speculate that genotyping of common risk variants for liver disease progression may be equally useful to gauge the likelihood of developing advanced liver disease in patients with secondary fatty liver disease.
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Zusi C, Morandi A, Maguolo A, Corradi M, Costantini S, Mosca A, Crudele A, Mantovani A, Alisi A, Miraglia Del Giudice E, Targher G, Maffeis C. Association between MBOAT7 rs641738 polymorphism and non-alcoholic fatty liver in overweight or obese children. Nutr Metab Cardiovasc Dis 2021; 31:1548-1555. [PMID: 33810963 DOI: 10.1016/j.numecd.2021.01.020] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/13/2020] [Revised: 01/22/2021] [Accepted: 01/23/2021] [Indexed: 01/10/2023]
Abstract
BACKGROUND AND AIM The association between non-alcoholic fatty liver (NAFL) and the variant rs641738 within the membrane bound O-acyltransferase domain-containing 7 (MBOAT7) gene is currently uncertain, especially in the paediatric population. We examined whether there is an association between this genetic variant and NAFL in a large multicentre, hospital-based cohort of Italian overweight/obese children. METHODS AND RESULTS We studied 1760 overweight or obese children [mean age (SD): 11.1(2.9) years, z-body mass index (zBMI) 3.2(0.9)], who underwent ultrasonography for the diagnosis of NAFL. A subgroup of these children (n = 182) also underwent liver biopsy. Genotyping of the MBOAT7 rs641738 polymorphism was performed by TaqMan-Based RT-PCR system in each subject. Overall, 1131 (64.3%) children had ultrasound-detected NAFL; 528 (30%) had rs641738 CC genotype, 849 (48.2%) had rs641738 CT genotype, and 383 (21.8%) had rs641738 TT genotype, respectively. In the whole cohort, the interaction of MBOAT7 genotypes with zBMI was not associated with NAFL after adjustment for age, sex, serum triglycerides, serum alanine aminotransferase levels and patatin-like phospholipase domain-containing protein-3 (PNPLA3) genotype (adjusted-odds ratio 1.02 [95% CI 0.98-1.06]). Similarly, no association was found between MBOAT7 genotypes and NAFL after stratification by obesity status. MBOAT7 genotypes were not associated with the presence of non-alcoholic steatohepatitis or the stage of liver fibrosis in a subgroup of 182 children with biopsy-proven NAFLD. CONCLUSIONS The results of this study did not show any significant contribution of MBOAT7 rs641738 polymorphism to the risk of having either NAFL on ultrasonography or NASH on histology in a large hospital-based cohort of Italian overweight/obese children.
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Affiliation(s)
- C Zusi
- Pediatric Diabetes and Metabolic Disorders Unit, Department of Surgery, Dentistry, Pediatrics and Gynaecology, University Hospital of Verona, Verona, Italy; Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University Hospital of Verona, Verona, Italy
| | - A Morandi
- Pediatric Diabetes and Metabolic Disorders Unit, Department of Surgery, Dentistry, Pediatrics and Gynaecology, University Hospital of Verona, Verona, Italy
| | - A Maguolo
- Pediatric Diabetes and Metabolic Disorders Unit, Department of Surgery, Dentistry, Pediatrics and Gynaecology, University Hospital of Verona, Verona, Italy
| | - M Corradi
- Pediatric Diabetes and Metabolic Disorders Unit, Department of Surgery, Dentistry, Pediatrics and Gynaecology, University Hospital of Verona, Verona, Italy
| | - S Costantini
- Pediatric Diabetes and Metabolic Disorders Unit, Department of Surgery, Dentistry, Pediatrics and Gynaecology, University Hospital of Verona, Verona, Italy
| | - A Mosca
- Hepatology, Gastroenterology and Nutrition Unit, "Bambino Gesù"Children's Hospital and IRCCS, Rome, Italy
| | - A Crudele
- Research Unit of Molecular Genetics of Complex Phenotypes, "Bambino Gesù" Children's Hospital and IRCCS, Rome, Italy
| | - A Mantovani
- Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University Hospital of Verona, Verona, Italy
| | - A Alisi
- Research Unit of Molecular Genetics of Complex Phenotypes, "Bambino Gesù" Children's Hospital and IRCCS, Rome, Italy
| | - E Miraglia Del Giudice
- Department of Woman, Child, and General and Specialized Surgery, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - G Targher
- Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University Hospital of Verona, Verona, Italy
| | - C Maffeis
- Pediatric Diabetes and Metabolic Disorders Unit, Department of Surgery, Dentistry, Pediatrics and Gynaecology, University Hospital of Verona, Verona, Italy.
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Gao F, Zheng KI, Chen SD, Lee DH, Wu XX, Wang XD, Targher G, Byrne CD, Chen YP, Kim W, Zheng MH. Individualized Polygenic Risk Score Identifies NASH in the Eastern Asia Region: A Derivation and Validation Study. Clin Transl Gastroenterol 2021; 12:e00321. [PMID: 33704100 PMCID: PMC7954375 DOI: 10.14309/ctg.0000000000000321] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/29/2020] [Accepted: 02/08/2021] [Indexed: 12/29/2022] Open
Abstract
INTRODUCTION Strong evidence indicates that multiple genetic and environmental risk factors play a role in the pathogenesis of nonalcoholic steatohepatitis (NASH). We aimed to develop and validate a novel nomogram, incorporating both genetic and clinical factors, for predicting NASH. METHODS A total of 1,070 Asian individuals with biopsy-confirmed nonalcoholic fatty liver disease (NAFLD) from 2 countries (China and South Korea) were recruited. The histological spectrum of NAFLD was classified according to the NASH clinical research network scoring system. The nomogram was developed in the Chinese training set (n = 402), and then, it was validated in both the Chinese internal validation set (n = 136) and the external Korean validation cohort (n = 532), respectively. RESULTS Sex, metabolic syndrome, insulin resistance, serum aspartate aminotransferase levels, and PNPLA3 (rs738409) and HSD17B13 (rs72613567) genetic variants were strongly associated with NASH. Based on their regression coefficients, we developed a nomogram with good discriminatory ability (area under the receiver operating characteristic curve: 0.81, 95% confidence interval [CI] 0.77-0.85) and good calibration (Hosmer-Lemeshow test, P = 0.794) for identifying NASH. In the 2 validation cohorts, the nomogram showed high area under the receiver operating characteristic curves (internal validation set: 0.80, 95% CI 0.72-0.88; external validation cohort: 0.76, 95% CI 0.72-0.80) and good calibration. DISCUSSION Our newly developed and externally validated nomogram, incorporating both genetic and clinical risk factors, may be conveniently used to predict NASH. Further validation studies in other ethnic groups are warranted to confirm its diagnostic utility to identify NASH, among patients with biopsy-proven NAFLD.
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Affiliation(s)
- Feng Gao
- Department of Gastroenterology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Kenneth I. Zheng
- NAFLD Research Center, Department of Hepatology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Sui-Dan Chen
- Department of Pathology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Dong Hyeon Lee
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Seoul National University College of Medicine, Seoul Metropolitan Government Boramae Medical Center, Seoul, Korea
| | - Xi-Xi Wu
- Department of Gastroenterology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Xiao-Dong Wang
- NAFLD Research Center, Department of Hepatology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Giovanni Targher
- Section of Endocrinology, Diabetes and Metabolism, Department of Medicine, University and Azienda Ospedaliera Universitaria Integrata of Verona, Verona, Italy
| | - Christopher D. Byrne
- Southampton National Institute for Health Research Biomedical Research Centre, University Hospital Southampton, Southampton General Hospital, Southampton, UK
| | - Yong-Ping Chen
- NAFLD Research Center, Department of Hepatology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
- Institute of Hepatology, Wenzhou Medical University, Wenzhou, China
- Key Laboratory of Diagnosis and Treatment for The Development of Chronic Liver Disease in Zhejiang Province, Wenzhou, China
| | - Won Kim
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Seoul National University College of Medicine, Seoul Metropolitan Government Boramae Medical Center, Seoul, Korea
| | - Ming-Hua Zheng
- NAFLD Research Center, Department of Hepatology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
- Institute of Hepatology, Wenzhou Medical University, Wenzhou, China
- Key Laboratory of Diagnosis and Treatment for The Development of Chronic Liver Disease in Zhejiang Province, Wenzhou, China
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Reply. Clin Gastroenterol Hepatol 2021; 19:413-414. [PMID: 33248097 DOI: 10.1016/j.cgh.2020.04.044] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/16/2020] [Accepted: 04/23/2020] [Indexed: 02/07/2023]
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Teo K, Abeysekera KWM, Adams L, Aigner E, Anstee QM, Banales JM, Banerjee R, Basu P, Berg T, Bhatnagar P, Buch S, Canbay A, Caprio S, Chatterjee A, Ida Chen YD, Chowdhury A, Daly AK, Datz C, de Gracia Hahn D, DiStefano JK, Dong J, Duret A, Emdin C, Fairey M, Gerhard GS, Guo X, Hampe J, Hickman M, Heintz L, Hudert C, Hunter H, Kelly M, Kozlitina J, Krawczyk M, Lammert F, Langenberg C, Lavine J, Li L, Lim HK, Loomba R, Luukkonen PK, Melton PE, Mori TA, Palmer ND, Parisinos CA, Pillai SG, Qayyum F, Reichert MC, Romeo S, Rotter JI, Im YR, Santoro N, Schafmayer C, Speliotes EK, Stender S, Stickel F, Still CD, Strnad P, Taylor KD, Tybjærg-Hansen A, Umano GR, Utukuri M, Valenti L, Wagenknecht LE, Wareham NJ, Watanabe RM, Wattacheril J, Yaghootkar H, Yki-Järvinen H, Young KA, Mann JP. rs641738C>T near MBOAT7 is associated with liver fat, ALT and fibrosis in NAFLD: A meta-analysis. J Hepatol 2021; 74:20-30. [PMID: 32882372 PMCID: PMC7755037 DOI: 10.1016/j.jhep.2020.08.027] [Citation(s) in RCA: 86] [Impact Index Per Article: 21.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/21/2020] [Revised: 07/29/2020] [Accepted: 08/20/2020] [Indexed: 12/14/2022]
Abstract
BACKGROUND & AIMS A common genetic variant near MBOAT7 (rs641738C>T) has been previously associated with hepatic fat and advanced histology in NAFLD; however, these findings have not been consistently replicated in the literature. We aimed to establish whether rs641738C>T is a risk factor across the spectrum of NAFLD and to characterise its role in the regulation of related metabolic phenotypes through a meta-analysis. METHODS We performed a meta-analysis of studies with data on the association between rs641738C>T genotype and liver fat, NAFLD histology, and serum alanine aminotransferase (ALT), lipids or insulin. These included directly genotyped studies and population-level data from genome-wide association studies (GWAS). We performed a random effects meta-analysis using recessive, additive and dominant genetic models. RESULTS Data from 1,066,175 participants (9,688 with liver biopsies) across 42 studies were included in the meta-analysis. rs641738C>T was associated with higher liver fat on CT/MRI (+0.03 standard deviations [95% CI 0.02-0.05], pz = 4.8×10-5) and diagnosis of NAFLD (odds ratio [OR] 1.17 [95% CI 1.05-1.3], pz = 0.003) in Caucasian adults. The variant was also positively associated with presence of advanced fibrosis (OR 1.22 [95% CI 1.03-1.45], pz = 0.021) in Caucasian adults using a recessive model of inheritance (CC + CT vs. TT). Meta-analysis of data from previous GWAS found the variant to be associated with higher ALT (pz = 0.002) and lower serum triglycerides (pz = 1.5×10-4). rs641738C>T was not associated with fasting insulin and no effect was observed in children with NAFLD. CONCLUSIONS Our study validates rs641738C>T near MBOAT7 as a risk factor for the presence and severity of NAFLD in individuals of European descent. LAY SUMMARY Fatty liver disease is a common condition where fat builds up in the liver, which can cause liver inflammation and scarring (including 'cirrhosis'). It is closely linked to obesity and diabetes, but some genes are also thought to be important. We did this study to see whether one specific change ('variant') in one gene ('MBOAT7') was linked to fatty liver disease. We took data from over 40 published studies and found that this variant near MBOAT7 is linked to more severe fatty liver disease. This means that drugs designed to work on MBOAT7 could be useful for treating fatty liver disease.
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Affiliation(s)
- Kevin Teo
- School of Clinical Medicine, University of Cambridge, Cambridge, UK
| | | | - Leon Adams
- Medical School, Faculty of Health and Medical Sciences, University of Western Australia, Perth, WA, Australia; Department of Hepatology, Sir Charles Gairdner Hospital, Perth, WA, Australia
| | - Elmar Aigner
- First Department of Medicine, Paracelsus Medical University Salzburg, Austria
| | - Quentin M Anstee
- Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK; Newcastle NIHR Biomedical Research Centre, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK
| | - Jesus M Banales
- Department on Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), CIBERehd, Ikerbasque, San Sebastian, Spain
| | | | | | - Thomas Berg
- Division of Hepatology, Department of Medicine II, Leipzig University Medical Center, Leipzig, Germany
| | | | - Stephan Buch
- Medical Department 1, University Hospital Dresden, Technische Universität Dresden (TU Dresden), Dresden, Germany
| | - Ali Canbay
- Gastroenterology, Hepatology and Infectiology, Otto-von-Guericke University Magdeburg, Magdeburg, Germany
| | - Sonia Caprio
- Yale University, Department of Pediatrics, New Haven, CT, USA
| | | | - Yii-Der Ida Chen
- The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, USA
| | - Abhijit Chowdhury
- Institute of Post Graduate Medical Education and Research, Kolkata, India
| | - Ann K Daly
- Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
| | - Christian Datz
- Department of Internal Medicine, General Hospital Oberndorf, Teaching Hospital of the Paracelsus Medical University Salzburg, Oberndorf, Austria
| | | | - Johanna K DiStefano
- Diabetes and Fibrotic Disease Unit Translational Genomics Research Institute (TGen), Phoenix, AZ, USA
| | - Jiawen Dong
- School of Clinical Medicine, University of Cambridge, Cambridge, UK
| | - Amedine Duret
- School of Clinical Medicine, University of Cambridge, Cambridge, UK
| | - Connor Emdin
- Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Boston, MA, USA
| | - Madison Fairey
- School of Clinical Medicine, University of Cambridge, Cambridge, UK
| | - Glenn S Gerhard
- Department of Medical Genetics and Molecular Biochemistry, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, USA
| | - Xiuqing Guo
- The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, USA
| | - Jochen Hampe
- Medical Department 1, University Hospital Dresden, Technische Universität Dresden (TU Dresden), Dresden, Germany
| | - Matthew Hickman
- MRC Integrative Epidemiology Unit (IEU), University of Bristol, Bristol, UK
| | - Lena Heintz
- Department of Medicine II, Saarland University Medical Center, Saarland University, Homburg, Germany
| | - Christian Hudert
- Department of Pediatric Gastroenterology, Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - Harriet Hunter
- School of Clinical Medicine, University of Cambridge, Cambridge, UK
| | | | - Julia Kozlitina
- Eugene McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Marcin Krawczyk
- Department of Medicine II, Saarland University Medical Center, Saarland University, Homburg, Germany; Laboratory of Metabolic Liver Diseases, Department of General, Transplant and Liver Surgery, Centre for Preclinical Research, Medical University of Warsaw, Warsaw, Poland
| | - Frank Lammert
- Department of Medicine II, Saarland University Medical Center, Saarland University, Homburg, Germany
| | - Claudia Langenberg
- MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge, Cambridge, UK
| | - Joel Lavine
- Department of Pediatrics, Columbia University, New York, NY, USA
| | - Lin Li
- BioStat Solutions LLC, Frederick, MD, USA
| | - Hong Kai Lim
- School of Clinical Medicine, University of Cambridge, Cambridge, UK
| | - Rohit Loomba
- NAFLD Research Center, Division of Gastroenterology and Epidemiology, University of California at San Diego, La Jolla, CA, USA
| | - Panu K Luukkonen
- Minerva Foundation Institute for Medical Research, Helsinki, Finland; Department of Medicine, University of Helsinki and Helsinki University Hospital, Helsinki, Finland; Yale University School of Medicine, New Haven, CT, USA
| | - Phillip E Melton
- School of Global Population Health, Faculty of Health and Medical Sciences, The University of Western Australia, Perth, WA, Australia; School of Pharmacy and Biomedical Sciences, Faculty of Health Sciences, Curtin University, Perth, WA, Australia; Menzies Institute for Medical Research, College of Health and Medicine, University of Tasmania, Hobart, Australia
| | - Trevor A Mori
- Medical School, Faculty of Health and Medical Sciences, University of Western Australia, Perth, WA, Australia
| | - Nicholette D Palmer
- Department of Biochemistry, Wake Forest School of Medicine, Winston-Salem, NC, USA
| | - Constantinos A Parisinos
- Institute of Health Informatics, Faculty of Population Health Sciences, University College London, London, UK
| | | | - Faiza Qayyum
- Department of Clinical Biochemistry, Rigshospitalet Copenhagen University Hospital, Copenhagen, Denmark
| | - Matthias C Reichert
- Department of Medicine II, Saarland University Medical Center, Saarland University, Homburg, Germany
| | - Stefano Romeo
- Department of Molecular and Clinical Medicine, University of Gothenburg, Gothenburg, Sweden; Cardiology Department, Sahlgrenska University Hospital, Gothenburg, Sweden; Clinical Nutrition Unit, Department of Medical and Surgical Sciences, University Magna Graecia, Catanzaro, Italy
| | - Jerome I Rotter
- The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, USA
| | - Yu Ri Im
- School of Clinical Medicine, University of Cambridge, Cambridge, UK
| | - Nicola Santoro
- Yale University, Department of Pediatrics, New Haven, CT, USA; Department of Medicine and Health Sciences 'V. Tiberio' University of Molise, Campobasso, Italy
| | - Clemens Schafmayer
- Department of Visceral and Thoracic Surgery, Kiel University, Kiel, Germany
| | - Elizabeth K Speliotes
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Michigan Health System, Ann Arbor, MI, USA; Department of Computational Medicine and Bioinformatics, University of Michigan Medical School, Ann Arbor, MI, USA
| | - Stefan Stender
- Department of Clinical Biochemistry, Rigshospitalet Copenhagen University Hospital, Copenhagen, Denmark
| | - Felix Stickel
- Department of Gastroenterology and Hepatology, University Hospital of Zurich, Zurich, Switzerland
| | | | - Pavel Strnad
- Medical Clinic III, University Hospital RWTH Aachen, Aachen, Germany
| | - Kent D Taylor
- The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, USA
| | - Anne Tybjærg-Hansen
- Department of Clinical Biochemistry, Rigshospitalet Copenhagen University Hospital, Copenhagen, Denmark
| | - Giuseppina Rosaria Umano
- Yale University, Department of Pediatrics, New Haven, CT, USA; Department of the Woman, the Child, of General and Specialized Surgery, University of Campania Luigi Vanvitelli, Naples, Italy
| | - Mrudula Utukuri
- School of Clinical Medicine, University of Cambridge, Cambridge, UK
| | - Luca Valenti
- Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy; Translational Medicine, Department of Transfusion Medicine and Hematology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico Milano, Milan, Italy
| | - Lynne E Wagenknecht
- Division of Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, NC, USA
| | - Nicholas J Wareham
- MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge, Cambridge, UK
| | - Richard M Watanabe
- Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Julia Wattacheril
- Department of Medicine, Center for Liver Disease and Transplantation, Columbia University College of Physicians and Surgeons, New York Presbyterian Hospital, New York, NY, USA
| | - Hanieh Yaghootkar
- Genetics of Complex Traits, College of Medicine and Health, University of Exeter, Exeter, UK
| | - Hannele Yki-Järvinen
- Minerva Foundation Institute for Medical Research, Helsinki, Finland; Department of Medicine, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Kendra A Young
- Department of Epidemiology, Colorado School of Public Health, University of Colorado Denver, Aurora, CO, USA
| | - Jake P Mann
- MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge, Cambridge, UK.
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