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Creasy KT, Mehta MB, Schneider CV, Park J, Zhang D, Shewale SV, Millar JS, Vujkovic M, Hand NJ, Titchenell PM, Baur JA, Rader DJ. Ppp1r3b is a metabolic switch that shifts hepatic energy storage from lipid to glycogen. SCIENCE ADVANCES 2025; 11:eado3440. [PMID: 40378221 PMCID: PMC12083521 DOI: 10.1126/sciadv.ado3440] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/28/2024] [Accepted: 04/10/2025] [Indexed: 05/18/2025]
Abstract
The PPP1R3B gene, encoding PPP1R3B protein, is critical for liver glycogen synthesis and maintaining blood glucose levels. Genetic variants affecting PPP1R3B expression are associated with several metabolic traits and liver disease, but the precise mechanisms are not fully understood. We studied the effects of both Ppp1r3b overexpression and deletion in mice and cell models and found that both changes in Ppp1r3b expression result in dysregulated metabolism and liver damage, with overexpression increasing liver glycogen stores, while deletion resulted in higher liver lipid accumulation. These patterns were confirmed in humans where variants increasing PPP1R3B expression had lower liver fat and decreased plasma lipids, whereas putative loss-of-function variants were associated with increased liver fat and elevated plasma lipids. These findings support that PPP1R3B is a crucial regulator of hepatic metabolism beyond glycogen synthesis and that genetic variants affecting PPP1R3B expression levels influence if hepatic energy is stored as glycogen or triglycerides.
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Affiliation(s)
- Kate Townsend Creasy
- Department of Biobehavioral Health Sciences, School of Nursing, University of Pennsylvania, Philadelphia, PA, USA
- Division of Translational Medicine and Human Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
- Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Minal B. Mehta
- Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Carolin V. Schneider
- Division of Translational Medicine and Human Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Joseph Park
- Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - David Zhang
- Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Swapnil V. Shewale
- Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - John S. Millar
- Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Marijana Vujkovic
- Division of Translational Medicine and Human Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Nicholas J. Hand
- Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Paul M. Titchenell
- Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
- Department of Physiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Joseph A. Baur
- Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
- Department of Physiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Daniel J. Rader
- Division of Translational Medicine and Human Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
- Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
- Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
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Chen VL, Vespasiani‐Gentilucci U. Integrating PNPLA3 into clinical risk prediction. Liver Int 2025; 45:e16103. [PMID: 39282715 PMCID: PMC11815612 DOI: 10.1111/liv.16103] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/26/2024] [Revised: 09/02/2024] [Accepted: 09/04/2024] [Indexed: 02/05/2025]
Abstract
The PNPLA3-rs738409-G variant was the first common variant associated with hepatic fat accumulation and progression of metabolic dysfunction-associated steatotic liver disease (MASLD). Nevertheless, to date, the clinical translation of this discovery has been minimal because it has not yet been clearly demonstrated where the genetic information may play an independent and additional role in clinical risk prediction. In this mini-review, we will discuss the most relevant evidence regarding the potential integration of the PNPLA3 variant into scores and algorithms for liver disease diagnostics and risk stratification, specifically focusing on MASLD but also extending to liver diseases of other etiologies. The PNPLA3 variant adds little in diagnosing the current state of the disease, whether in terms of presence/absence of metabolic dysfunction-associated steatohepatitis or the stage of fibrosis. While it can play an important role in prediction, allowing for the early definition of risk profiles that enable tailored monitoring and interventions over time, this is most valuable when applied to populations with relatively high pre-test probability of having significant fibrosis based on either non-invasive tests (e.g. Fibrosis-4) or demographics (e.g. diabetes). Indeed, in this context, integrating FIB4 with the PNPLA3 genotype can refine risk stratification, though there is still no evidence that genetic information adds to liver stiffness determined by elastography. Similarly, in patients with known liver cirrhosis, knowing the PNPLA3 genotype can play a role in predicting the risk of hepatocellular carcinoma, while more doubts remain about the risk of decompensation.
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Affiliation(s)
- Vincent L. Chen
- Division of Gastroenterology and Hepatology, Department of Internal MedicineUniversity of Michigan Medical SchoolAnn ArborMichiganUSA
| | - Umberto Vespasiani‐Gentilucci
- Research Unit of HepatologyUniversità Campus Bio‐Medico di RomeRomeItaly
- Hepatology and Clinical Medicine UnitFondazione Policlinico Universitario Campus‐Biomedico di RomaRomeItaly
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Yang X, Pan Y, Zhang Y, Meng Y, Tong T, Zhao M. Association of systemic immune-inflammation index (SII) with risk of psoriasis: a cross-sectional analysis of National Health and Nutrition Examination Survey 2011-2014. Eur J Med Res 2025; 30:58. [PMID: 39881406 PMCID: PMC11776211 DOI: 10.1186/s40001-025-02304-0] [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: 02/16/2024] [Accepted: 01/16/2025] [Indexed: 01/31/2025] Open
Abstract
BACKGROUND The systemic immune-inflammation index (SII) is an emerging marker of inflammation, and the onset of psoriasis is associated with inflammation. The aim of our study was to investigate the potential impact of SII on the incidence rate of adult psoriasis. METHODS We conducted a cross-sectional study based on the National Health and Nutrition Examination Survey (NHANES) 2011-2014 data sets. Multiple logistic regression analyses with appropriate covariates adjustment were the major methods in this study. Subgroup analyses were conducted by age, gender, race, smoking status, alcohol consumption, history of heart attack, stroke, coronary heart disease and diabetes. Interactions among these variables were also detected. We further utilized smooth curve fitting to explore potential nonlinear associations between SII and psoriasis across different subgroups. The receiver operating characteristic curve analysis was used to assess the diagnostic value of SII for psoriasis in the general population and diabetic individuals. Multiple imputation was adopted as sensitivity analysis to address potential bias due to missing data. RESULTS 9314 participants (≥ 20 years) were included. A significant positive association was observed between SII and psoriasis (OR = 1.56; P = 0.0069). Subgroup analysis revealed significant positive association in males (OR = 1.52; P = 0.0288), females (OR = 1.61; P = 0.0322), Non-Hispanic Whites (OR = 1.55; P = 0.0190), people aged 40-59 years (OR = 1.98; P = 0.0386), diabetics (OR = 3.40; P = 0.0088), and overweight participants (OR = 1.80; P = 0.0034). SII had a higher predictive value for psoriasis in diabetic patients (AUC = 0.62; 95% CI [0.55, 0.70]). In stroke patients, SII was negatively correlated with the occurrence of psoriasis, and interaction test suggested the effect of SII on psoriasis was significantly modified by stroke (P = 0.0003). Nonlinear relationships between SII and psoriasis were observed in participants aged 20 to 39, former smokers, current drinkers, individuals with or without heart attack, those without coronary heart disease, and overweight participants. CONCLUSIONS SII was positively associated with psoriasis. Testing for SII levels may help to identify the onset of psoriasis early.
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Affiliation(s)
- Xuan Yang
- The Department of Pediatrics, The Third Xiangya Hospital of Central South University, Changsha, 410013, Hunan, China
- The Department of Dermatology, Xiangya Hospital of Central South University, Changsha, 410083, Hunan, China
| | - Yuxin Pan
- The Department of Pediatrics, The Third Xiangya Hospital of Central South University, Changsha, 410013, Hunan, China
| | - Yang Zhang
- The Department of Pediatrics, The Third Xiangya Hospital of Central South University, Changsha, 410013, Hunan, China
| | - Yang Meng
- The Department of Pediatrics, The Third Xiangya Hospital of Central South University, Changsha, 410013, Hunan, China
| | - Tang Tong
- Academician Workstation, Changsha Medical University, Changsha, 410219, Hunan, China
| | - Mingyi Zhao
- The Department of Pediatrics, The Third Xiangya Hospital of Central South University, Changsha, 410013, Hunan, China.
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Pei Y, Goh GBB. Genetic Risk Factors for Metabolic Dysfunction-Associated Steatotic Liver Disease. Gut Liver 2025; 19:8-18. [PMID: 39774124 PMCID: PMC11736312 DOI: 10.5009/gnl240407] [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] [Received: 09/23/2024] [Revised: 11/04/2024] [Accepted: 11/07/2024] [Indexed: 01/11/2025] Open
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD), is the most common cause of liver disease, and its burden on health systems worldwide continues to rise at an alarming rate. MASLD is a complex disease in which the interactions between susceptible genes and the environment influence the disease phenotype and severity. Advances in human genetics over the past few decades have provided new opportunities to improve our understanding of the multiple pathways involved in the pathogenesis of MASLD. Notably, the PNPLA3, TM6SF2, GCKR, MBOAT7 and HSD17B13 single nucleotide polymorphisms have been demonstrated to be robustly associated with MASLD development and disease progression. These genetic variants play crucial roles in lipid droplet remodeling, secretion of hepatic very low-density lipoprotein and lipogenesis, and understanding the biology has brought new insights to this field. This review discusses the current body of knowledge regarding these genetic drivers and how they can lead to development of MASLD, the complex interplay with metabolic factors such as obesity, and how this information has translated clinically into the development of risk prediction models and possible treatment targets.
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Affiliation(s)
- Yiying Pei
- Department of Gastroenterology and Hepatology, Singapore General Hospital, Singapore
- Medicine Academic Clinical Program, Duke-National University of Singapore (Duke-NUS) Medical School, Singapore
| | - George Boon-Bee Goh
- Department of Gastroenterology and Hepatology, Singapore General Hospital, Singapore
- Medicine Academic Clinical Program, Duke-National University of Singapore (Duke-NUS) Medical School, Singapore
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Chen VL, Brady GF. Recent advances in MASLD genetics: Insights into disease mechanisms and the next frontiers in clinical application. Hepatol Commun 2025; 9:e0618. [PMID: 39774697 PMCID: PMC11717516 DOI: 10.1097/hc9.0000000000000618] [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: 11/05/2024] [Accepted: 11/14/2024] [Indexed: 01/11/2025] Open
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common chronic liver disease in the world and a growing cause of liver-related morbidity and mortality. Yet, at the same time, our understanding of the pathophysiology and genetic underpinnings of this increasingly common yet heterogeneous disease has increased dramatically over the last 2 decades, with the potential to lead to meaningful clinical interventions for patients. We have now seen the first pharmacologic therapy approved for the treatment of MASLD, and multiple other potential treatments are currently under investigation-including gene-targeted RNA therapies that directly extend from advances in MASLD genetics. Here we review recent advances in MASLD genetics, some of the key pathophysiologic insights that human genetics has provided, and the ways in which human genetics may inform our clinical practice in the field of MASLD in the near future.
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Ma G, Xu B, Wang Z, Duan W, Chen X, Zhu L, Yang B, Zhang D, Qin X, Yin H, Wei X. Non-linear association of sleep duration with osteoarthritis among U.S. middle-aged and older adults. BMC Public Health 2024; 24:3565. [PMID: 39716177 DOI: 10.1186/s12889-024-21140-1] [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: 10/07/2024] [Accepted: 12/18/2024] [Indexed: 12/25/2024] Open
Abstract
BACKGROUND The duration of sleep is linked to a range of disorders. Osteoarthritis (OA) stands as one of the most prevalent forms of arthritis and serves as a leading cause of disability. The correlation between the duration of sleep and OA remains ambiguous. Research indicates that waist circumference correlates with sleep duration and OA, respectively. This study aimed to investigate the association of sleep duration with OA and the mediated effect of waist circumference. METHODS The study sample comprised adults who were participants in the National Health and Nutrition Examination Survey (NHANES) between 2011 and 2018. Insufficient sleep is characterized by a duration of less than seven hours, whereas 7-8 h is considered appropriate, and 9 h or more is categorized as a long sleep duration. Three models were employed in this study. Model 1 was not adjusted for any covariates, while Model 2 was adjusted for sex, age, and race. Model 3 has been adjusted to account for all covariates. Utilizing multivariable logistic regression, subgroup analysis, interaction tests and smoothing curve fitting, the correlation between sleep duration and OA was explored. The mediating effect of waist circumference on the association between sleep duration and OA was investigated through mediation analysis. RESULTS In this study, 9380 did not have OA, while 2424 were diagnosed with the ailment. After multivariable adjustment, the odds ratios (OR) for OA were 1.19 (95% CI 1.06, 1.34; P = 0.0026) for people with insufficient sleep duration and 1.18 (95% CI 1.03, 1.35 P = 0.0142) for participants with long sleep duration. Sleep duration and the incidence of OA were found to be related in a U-shaped manner. Additionally, 12.1% of the correlation between sleep duration and OA appeared to be mediated by waist circumference. CONCLUSIONS Increased OA was found to be correlated in a U-shaped manner with sleep duration in the middle-aged and elderly cohorts. Both insufficient and long sleep duration contribute to an elevated risk of developing OA. A potential mediating factor in the association between OA and sleep duration is waist circumference. Focus on sleep health and visceral obesity in middle-aged and older adults is necessary.
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Affiliation(s)
- Guoliang Ma
- Wangjing Hospital, China Academy of Chinese Medical Sciences, No. 6, Zhonghuan South Road, Chaoyang District, Beijing, 100102, China
| | - Bo Xu
- Wangjing Hospital, China Academy of Chinese Medical Sciences, No. 6, Zhonghuan South Road, Chaoyang District, Beijing, 100102, China
| | - Zhizhuang Wang
- Wangjing Hospital, China Academy of Chinese Medical Sciences, No. 6, Zhonghuan South Road, Chaoyang District, Beijing, 100102, China
| | - Weili Duan
- Nanyang Hospital of Traditional Chinese Medicine (Dushan Campus), Henan , 473003, China
| | - Xin Chen
- Wangjing Hospital, China Academy of Chinese Medical Sciences, No. 6, Zhonghuan South Road, Chaoyang District, Beijing, 100102, China
| | - Liguo Zhu
- Wangjing Hospital, China Academy of Chinese Medical Sciences, No. 6, Zhonghuan South Road, Chaoyang District, Beijing, 100102, China
- Beijing Key Laboratory of Bone Setting Technology of Traditional Chinese Medicine, Beijing, 100700, China
| | - Bowen Yang
- Wangjing Hospital, China Academy of Chinese Medical Sciences, No. 6, Zhonghuan South Road, Chaoyang District, Beijing, 100102, China
| | - Dian Zhang
- Wangjing Hospital, China Academy of Chinese Medical Sciences, No. 6, Zhonghuan South Road, Chaoyang District, Beijing, 100102, China
| | - Xiaokuan Qin
- Wangjing Hospital, China Academy of Chinese Medical Sciences, No. 6, Zhonghuan South Road, Chaoyang District, Beijing, 100102, China
| | - He Yin
- Wangjing Hospital, China Academy of Chinese Medical Sciences, No. 6, Zhonghuan South Road, Chaoyang District, Beijing, 100102, China.
| | - Xu Wei
- Wangjing Hospital, China Academy of Chinese Medical Sciences, No. 6, Zhonghuan South Road, Chaoyang District, Beijing, 100102, China.
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Zheng YF, Guo YM, Song CJ, Liu GC, Chen SY, Guo XG, Lin LH. A cross-sectional study on the relationship between dietary fiber and endometriosis risk based on NHANES 1999-2006. Sci Rep 2024; 14:28502. [PMID: 39557911 PMCID: PMC11574079 DOI: 10.1038/s41598-024-79746-9] [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: 03/21/2024] [Accepted: 11/12/2024] [Indexed: 11/20/2024] Open
Abstract
Endometriosis is a chronic inflammatory disease and an estrogen-dependent disease, so dietary factors that can modulate estrogen activity may be clinically important. Dietary fiber, widely distributed in vegetables and fruits, is closely associated with a plant-based diet. Therefore, this study aims to analyze and explore the relationship between dietary fiber intake and the risk of endometriosis providing insights for future clinical significance and treatment approaches. This cross-sectional study obtained data from the National Health and Nutrition Examination Survey (NHANES) 1999-2006 for women aged 20-54 years. A total of 2840 subjects were finally included for analysis, 2599 (91.51%) in the non-endometriosis group and 241 (8.49%) in the endometriosis group. The study used dietary fibre intake as exposure variable and endometriosis risk as outcome variable. Through the use of multiple regression modelling, subgroup analyses, smoothed curve fitting, and threshold effect tests, we uncovered a significant link between exposure and outcome. In Model 2 (Multiple regression equation model after adjusting all confounding variables), after adjusting for confounders, dietary fiber intake was negatively associated with the likelihood of developing endometriosis(OR = 0.588, 95% CI = 0.360-0.959, p = 0.041). In subgroup analyses stratified by age, race, BMI, educational level, hypertension, diabetes,and hyperlipidemia, significant interactions were visualised from smoothed fitted curves. In the cross-sectional study, a connection was observed between a higher intake of dietary fiber and a decreased risk of endometriosis.
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Affiliation(s)
- Ya-Fang Zheng
- Department of Obstetrics and Gynecology, Center for Reproductive Medicine, Guangdong Provincial Key Laboratory of Major Obstetric Diseases; Guangdong Provincial Clinical Research Center for Obstetrics and Gynecology; Guangdong-Hong Kong-Macao Greater Bay Area Higher Education Joint Laboratory of Maternal-Fetal Medicine; The Third Affiliated Hospital, Guangzhou Medical University, Guangzhou, China
- Department of Clinical Medicine, The Third School of Clinical Medicine, Guangzhou Medical University, Guangzhou, 511436, China
| | - Yu-Miao Guo
- Department of Obstetrics and Gynecology, Center for Reproductive Medicine, Guangdong Provincial Key Laboratory of Major Obstetric Diseases; Guangdong Provincial Clinical Research Center for Obstetrics and Gynecology; Guangdong-Hong Kong-Macao Greater Bay Area Higher Education Joint Laboratory of Maternal-Fetal Medicine; The Third Affiliated Hospital, Guangzhou Medical University, Guangzhou, China
- Department of Clinical Medicine, The Third School of Clinical Medicine, Guangzhou Medical University, Guangzhou, 511436, China
| | - Chu-Jun Song
- Department of Obstetrics and Gynecology, Center for Reproductive Medicine, Guangdong Provincial Key Laboratory of Major Obstetric Diseases; Guangdong Provincial Clinical Research Center for Obstetrics and Gynecology; Guangdong-Hong Kong-Macao Greater Bay Area Higher Education Joint Laboratory of Maternal-Fetal Medicine; The Third Affiliated Hospital, Guangzhou Medical University, Guangzhou, China
- Department of Clinical Medicine, The Third School of Clinical Medicine, Guangzhou Medical University, Guangzhou, 511436, China
| | - Gui-Chao Liu
- Department of Obstetrics and Gynecology, Center for Reproductive Medicine, Guangdong Provincial Key Laboratory of Major Obstetric Diseases; Guangdong Provincial Clinical Research Center for Obstetrics and Gynecology; Guangdong-Hong Kong-Macao Greater Bay Area Higher Education Joint Laboratory of Maternal-Fetal Medicine; The Third Affiliated Hospital, Guangzhou Medical University, Guangzhou, China
- Department of Public Utilities Management, School of Health Management, Guangzhou Medical University, Guangzhou, 511436, China
| | - Shi-Yi Chen
- Department of Obstetrics and Gynecology, Center for Reproductive Medicine, Guangdong Provincial Key Laboratory of Major Obstetric Diseases; Guangdong Provincial Clinical Research Center for Obstetrics and Gynecology; Guangdong-Hong Kong-Macao Greater Bay Area Higher Education Joint Laboratory of Maternal-Fetal Medicine; The Third Affiliated Hospital, Guangzhou Medical University, Guangzhou, China
- Department of Clinical Medicine, The Third School of Clinical Medicine, Guangzhou Medical University, Guangzhou, 511436, China
| | - Xu-Guang Guo
- Department of Obstetrics and Gynecology, Center for Reproductive Medicine, Guangdong Provincial Key Laboratory of Major Obstetric Diseases; Guangdong Provincial Clinical Research Center for Obstetrics and Gynecology; Guangdong-Hong Kong-Macao Greater Bay Area Higher Education Joint Laboratory of Maternal-Fetal Medicine; The Third Affiliated Hospital, Guangzhou Medical University, Guangzhou, China.
- Department of Clinical Medicine, The Third School of Clinical Medicine, Guangzhou Medical University, Guangzhou, 511436, China.
- Guangzhou Key Laboratory for Clinical Rapid Diagnosis and Early Warning of Infectious Diseases, Kingmed School of Laboratory Medicine, Guangzhou Medical University, Guangzhou, 510000, China.
- Department of Clinical Laboratory Medicine, Guangdong Provincial Key Laboratory of Major Obstetric Diseases, Guangdong Provincial Clinical Research Center for Obstetrics and Gynecology; The Third Affiliated Hospital, Guangzhou Medical University, Guangzhou, 510150, China.
| | - Li-Hong Lin
- Department of Obstetrics and Gynecology, Center for Reproductive Medicine, Guangdong Provincial Key Laboratory of Major Obstetric Diseases; Guangdong Provincial Clinical Research Center for Obstetrics and Gynecology; Guangdong-Hong Kong-Macao Greater Bay Area Higher Education Joint Laboratory of Maternal-Fetal Medicine; The Third Affiliated Hospital, Guangzhou Medical University, Guangzhou, China.
- Department of Clinical Medicine, The Third School of Clinical Medicine, Guangzhou Medical University, Guangzhou, 511436, China.
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Reid MV, Fredickson G, Mashek DG. Mechanisms coupling lipid droplets to MASLD pathophysiology. Hepatology 2024:01515467-990000000-01067. [PMID: 39475114 DOI: 10.1097/hep.0000000000001141] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/15/2024] [Accepted: 10/17/2024] [Indexed: 01/03/2025]
Abstract
Hepatic steatosis, the buildup of neutral lipids in lipid droplets (LDs), is commonly referred to as metabolic dysfunction-associated steatotic liver disease when alcohol or viral infections are not involved. Metabolic dysfunction-associated steatotic liver disease encompasses simple steatosis and the more severe metabolic dysfunction-associated steatohepatitis, characterized by inflammation, hepatocyte injury, and fibrosis. Previously viewed as inert markers of disease, LDs are now understood to play active roles in disease etiology and have significant nonpathological and pathological functions in cell signaling and function. These dynamic properties of LDs are tightly regulated by hundreds of proteins that coat the LD surface, controlling lipid metabolism, trafficking, and signaling. The following review highlights various facets of LD biology with the primary goal of discussing key mechanisms through which LDs promote the development of advanced liver diseases, including metabolic dysfunction-associated steatohepatitis.
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Affiliation(s)
- Mari V Reid
- Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, Minnesota, USA
| | - Gavin Fredickson
- Department of Integrated Biology and Physiology, University of Minnesota, Minneapolis, Minnesota, USA
| | - Douglas G Mashek
- Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, Minnesota, USA
- Department of Medicine, Division of Diabetes, Endocrinology and Metabolism, University of Minnesota, Minneapolis, Minnesota, USA
- Institute on the Biology of Aging and Metabolism, University of Minnesota, Minneapolis, Minnesota, USA
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Ying B, Liu X, Yang C, Xu J, Chen Y. Gender-specific association between a lipid composite index and asthma among US adults: insights from a population-based study. Lipids Health Dis 2024; 23:353. [PMID: 39478611 PMCID: PMC11523672 DOI: 10.1186/s12944-024-02338-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2024] [Accepted: 10/22/2024] [Indexed: 11/03/2024] Open
Abstract
BACKGROUND Abnormalities in lipid metabolism are common among adult asthmatics. However, the precise directionality linking asthma to blood lipid levels remains controversial. Our study aimed to evaluate the association between the Non-HDL to HDL Ratio (NHHR), a lipid composite index, and asthma prevalence among the adult population in the United States. METHODS Utilizing adult participants' data from the National Health and Nutrition Examination Survey (NHANES) spanning the years 2009 to 2018, the study employed a multivariable logistic regression model, adjusting for covariables, to establish the relationship between NHHR levels and the prevalence of asthma. Furthermore, smoothing curve fitting and subgroup analyses were conducted to investigate the robustness of this association. RESULTS This study included 26,023 adult individuals (mean age = 49.63 ± 17.66). In the fully adjusted model, a significant inverse association was observed between log-transformed NHHR values and asthma prevalence (OR = 0.85, 95% CI: 0.79-0.93). Subgroup analysis revealed that gender served as a modulator, altering the association between NHHR levels and asthma prevalence. A more pronounced negative association between lnNHHR and asthma prevalence was noted among male participants [(Male: OR = 0.78, 95% CI: 0.69-0.88) vs. (Female: OR = 0.92, 95% CI: 0.83-1.03), P for interaction = 0.0313]. CONCLUSIONS Our study revealed an inverse association between NHHR levels and the prevalence of asthma in the US adult population, which is influenced by gender. NHHR measurement may be a potential tool for early identification and prediction of adult asthmatics in specific populations.
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Affiliation(s)
- Bufan Ying
- School of Basic Medical Sciences, Naval Medical University, No 800. Xiangyin Road, Yangpu, Shanghai, 200433, China
| | - Xiaoxin Liu
- Department of Nephrology, Liyuan Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430077, Hubei, China
| | - Chengming Yang
- School of Basic Medical Sciences, Naval Medical University, No 800. Xiangyin Road, Yangpu, Shanghai, 200433, China
| | - Jinfang Xu
- Department of Health Statistics, Naval Medical University, No 800. Xiangyin Road, Yangpu, Shanghai, 200433, China.
| | - Ying Chen
- NHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of Metabolic Diseases, Chu Hsien-I Memorial Hospital & Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, 300134, China.
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Qiu L, Ren Y, Li J, Li M, Li W, Qin L, Ning C, Zhang J, Gao F. Association of systemic immune inflammatory index with obesity and abdominal obesity: A cross-sectional study from NHANES. Nutr Metab Cardiovasc Dis 2024; 34:2409-2419. [PMID: 39069464 DOI: 10.1016/j.numecd.2024.06.003] [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] [Received: 03/27/2024] [Revised: 05/31/2024] [Accepted: 06/03/2024] [Indexed: 07/30/2024]
Abstract
BACKGROUND AND AIM Our aim was to explore the potential relationship between SII and obesity, as well as abdominal obesity. METHODS AND RESULTS We utilized a weighted multivariable logistic regression model to investigate the relationship between SII and obesity, as well as abdominal obesity. Generalized additive models were employed to test for non-linear associations. Subsequently, we constructed a two-piecewise linear regression model and conducted a recursive algorithm to calculate inflection points. Additionally, subgroup analyses and interaction tests were performed. A total of 7,880 U.S. adult participants from NHANES 2011-2018 were recruited for this study. In the regression model adjusted for all confounding variables, the odds ratios (95% confidence intervals) for the association between SII/100 and obesity, as well as abdominal obesity, were 1.03 (1.01, 1.06) and 1.04 (1.01, 1.08) respectively. There was a non-linear and reverse U-shaped association between SII/100 and obesity, as well as abdominal obesity, with inflection points at 7.32 and 9.98 respectively. Significant positive correlations were observed before the inflection points, while significant negative correlations were found after the inflection points. There was a statistically significant interaction in the analysis of age, hypertension, and diabetes. Moreover, a notable interaction is observed between SII/100 and abdominal obesity within non-Hispanic Asian populations. CONCLUSIONS In adults from the United States, there is a positive correlation between SII and the high risk of obesity, as well as abdominal obesity. Further large-scale prospective studies are needed to analyze the role of SII in obesity and abdominal obesity.
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Affiliation(s)
- Linjie Qiu
- Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Yan Ren
- Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Jixin Li
- Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Meijie Li
- Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Wenjie Li
- Shanxi University of Chinese Medicine, Shanxi, China
| | - Lingli Qin
- Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Chunhui Ning
- Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Jin Zhang
- Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China.
| | - Feng Gao
- Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China.
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11
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Li J, Ma X, Yin C. Proteome-wide Mendelian randomization identifies potential therapeutic targets for nonalcoholic fatty liver diseases. Sci Rep 2024; 14:11814. [PMID: 38782984 PMCID: PMC11116402 DOI: 10.1038/s41598-024-62742-4] [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: 02/18/2024] [Accepted: 05/21/2024] [Indexed: 05/25/2024] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is the predominant cause of liver pathology. Current evidence highlights plasma proteins as potential therapeutic targets. However, their mechanistic roles in NAFLD remain unclear. This study investigated the involvement of specific plasma proteins and intermediate risk factors in NAFLD progression. Two-sample Mendelian randomization (MR) analysis was conducted to examine the association between plasma proteins and NAFLD. Colocalization analysis determined the shared causal variants between the identified proteins and NAFLD. The MR analysis was applied separately to proteins, risk factors, and NAFLD. Mediator shares were computed by detecting the correlations among these elements. Phenome-wide association studies (phewas) were utilized to assess the safety implications of targeting these proteins. Among 1,834 cis-protein quantitative trait loci (cis-pQTLs), after-FDR correction revealed correlations between the plasma levels of four gene-predicted proteins (CSPG3, CILP2, Apo-E, and GCKR) and NAFLD. Colocalization analysis indicated shared causal variants for CSPG3 and GCKR in NAFLD (posterior probability > 0.8). Out of the 22 risk factors screened for MR analysis, only 8 showed associations with NAFLD (p ≤ 0.05), while 4 linked to CSPG3 and GCKR. The mediator shares for these associations were calculated separately. Additionally, reverse MR analysis was performed on the pQTLs, risk factors, and NAFLD, which exhibited a causal relationship with forward MR analysis. Finally, phewas summarized the potential side effects of associated-targeting proteins, including CSPG3 and GCKR. Our research emphasized the potential therapeutic targets for NAFLD and provided modifiable risk factors for preventing NAFLD.
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Affiliation(s)
- Junhang Li
- Department of Ultrasonography, Dali Prefecture Third People's Hospital, Dali Prefecture, Yunnan Province, China
| | - Xiang Ma
- Chongqing Medical University, Chongqing, China
| | - Cuihua Yin
- Department of Ultrasonography, Dali Prefecture Third People's Hospital, Dali Prefecture, Yunnan Province, China.
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12
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Hu B, Wang Y, Feng J, Hou L. The association between flavonoids intake and hypertension in U.S. adults: A cross-sectional study from The National Health and Nutrition Examination Survey. J Clin Hypertens (Greenwich) 2024; 26:573-583. [PMID: 38630898 PMCID: PMC11088421 DOI: 10.1111/jch.14807] [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: 11/20/2023] [Revised: 02/27/2024] [Accepted: 03/18/2024] [Indexed: 04/19/2024]
Abstract
Although in vitro experiments have demonstrated the potential of flavonoid compounds in regulating blood pressure, there is still a lack of evidence from large population studies. We conducted a cross-sectional study using the National Health and Nutrition Examination Survey to investigate the relationship between flavonoid intake levels (natural log transformation) and hypertension events. A total of 15 752 participants aged over 20 years were included, and a weighted multivariable logistic regression analysis was performed to explore the relationship between total flavonoids, five sub types intake, and hypertension events. Smooth curve fitting was used to explore potential nonlinear relationships. Higher total flavonoids intake was associated with a lower risk of hypertension than the lowest group. The adjusted odds ratios (95% CIs) were 0.79 (0.70-0.88) for total flavonoids intake. Elevated total flavonoids intake levels were significantly and linearly associated with a lower risk of hypertension. For each unit increase in the total flavonoids intake level, the adjusted ORs for risk of hypertension decrease by 5% (OR 0.95; 95% CI, 0.92-0.98). In addition, in restricted cubic spline regression, we found that flavan-3-ols, anthocyanidins, and flavonols intake were linearly and negatively related to prevalence of hypertension. Flavones intake showed nonlinear associations with prevalence of hypertension with inflection points of -1.90. Within a certain range, a negative correlation exists between flavonoids intake and hypertension events. This finding provides insights into dietary modifications in the prevention of hypertension.
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Affiliation(s)
- Ben Hu
- Department of CardiologyThe Second People's Hospital of Hefei, Hefei Hospital Affiliated to Anhui Medical UniversityHefeiAnhuiChina
- The Fifth Clinical Medical School of Anhui Medical UniversityHefeiAnhuiChina
| | - Yan Wang
- Academy of Medical SciencesShanxi Medical UniversityTaiyuanShanxi ProvinceChina
| | - Jun Feng
- Department of CardiologyThe Second People's Hospital of Hefei, Hefei Hospital Affiliated to Anhui Medical UniversityHefeiAnhuiChina
| | - Linlin Hou
- Department of CardiologyThe Second People's Hospital of Hefei, Hefei Hospital Affiliated to Anhui Medical UniversityHefeiAnhuiChina
- The Fifth Clinical Medical School of Anhui Medical UniversityHefeiAnhuiChina
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13
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Smagris E, Shihanian LM, Mintah IJ, Bigdelou P, Livson Y, Brown H, Verweij N, Hunt C, Johnson RO, Greer TJ, Hartford SA, Hindy G, Sun L, Nielsen JB, Halasz G, Lotta LA, Murphy AJ, Sleeman MW, Gusarova V. Divergent role of Mitochondrial Amidoxime Reducing Component 1 (MARC1) in human and mouse. PLoS Genet 2024; 20:e1011179. [PMID: 38437227 PMCID: PMC10939284 DOI: 10.1371/journal.pgen.1011179] [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] [Received: 10/01/2023] [Revised: 03/14/2024] [Accepted: 02/09/2024] [Indexed: 03/06/2024] Open
Abstract
Recent human genome-wide association studies have identified common missense variants in MARC1, p.Ala165Thr and p.Met187Lys, associated with lower hepatic fat, reduction in liver enzymes and protection from most causes of cirrhosis. Using an exome-wide association study we recapitulated earlier MARC1 p.Ala165Thr and p.Met187Lys findings in 540,000 individuals from five ancestry groups. We also discovered novel rare putative loss of function variants in MARC1 with a phenotype similar to MARC1 p.Ala165Thr/p.Met187Lys variants. In vitro studies of recombinant human MARC1 protein revealed Ala165Thr substitution causes protein instability and aberrant localization in hepatic cells, suggesting MARC1 inhibition or deletion may lead to hepatoprotection. Following this hypothesis, we generated Marc1 knockout mice and evaluated the effect of Marc1 deletion on liver phenotype. Unexpectedly, our study found that whole-body Marc1 deficiency in mouse is not protective against hepatic triglyceride accumulation, liver inflammation or fibrosis. In attempts to explain the lack of the observed phenotype, we discovered that Marc1 plays only a minor role in mouse liver while its paralogue Marc2 is the main Marc family enzyme in mice. Our findings highlight the major difference in MARC1 physiological function between human and mouse.
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Affiliation(s)
- Eriks Smagris
- Regeneron Pharmaceuticals, Tarrytown, New York, Unites States of America
| | - Lisa M. Shihanian
- Regeneron Pharmaceuticals, Tarrytown, New York, Unites States of America
| | - Ivory J. Mintah
- Regeneron Pharmaceuticals, Tarrytown, New York, Unites States of America
| | - Parnian Bigdelou
- Regeneron Pharmaceuticals, Tarrytown, New York, Unites States of America
| | - Yuliya Livson
- Regeneron Pharmaceuticals, Tarrytown, New York, Unites States of America
| | - Heather Brown
- Regeneron Pharmaceuticals, Tarrytown, New York, Unites States of America
| | - Niek Verweij
- Regeneron Pharmaceuticals, Tarrytown, New York, Unites States of America
| | - Charleen Hunt
- Regeneron Pharmaceuticals, Tarrytown, New York, Unites States of America
| | | | - Tyler J. Greer
- Regeneron Pharmaceuticals, Tarrytown, New York, Unites States of America
| | | | - George Hindy
- Regeneron Pharmaceuticals, Tarrytown, New York, Unites States of America
| | - Luanluan Sun
- Regeneron Pharmaceuticals, Tarrytown, New York, Unites States of America
| | - Jonas B. Nielsen
- Regeneron Pharmaceuticals, Tarrytown, New York, Unites States of America
| | - Gabor Halasz
- Regeneron Pharmaceuticals, Tarrytown, New York, Unites States of America
| | - Luca A. Lotta
- Regeneron Pharmaceuticals, Tarrytown, New York, Unites States of America
| | - Andrew J. Murphy
- Regeneron Pharmaceuticals, Tarrytown, New York, Unites States of America
| | - Mark W. Sleeman
- Regeneron Pharmaceuticals, Tarrytown, New York, Unites States of America
| | - Viktoria Gusarova
- Regeneron Pharmaceuticals, Tarrytown, New York, Unites States of America
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14
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Liu S, Wu S, Bao X, Ji J, Ye Y, Guo J, Liu J, Wang X, Zhang Y, Hao D, Huang D. Changes in Blood Pressure is Associated with Bone Loss in US Adults: A Cross-Sectional Study from NHANES 2005-2018. Calcif Tissue Int 2024; 114:276-285. [PMID: 38261009 DOI: 10.1007/s00223-023-01176-y] [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: 11/17/2023] [Accepted: 11/19/2023] [Indexed: 01/24/2024]
Abstract
Hypertension and osteoporosis are common geriatric diseases, sharing similar risk factors. This study aims to investigate this association and explore relatively mixed variables. Our study included 12,787 eligible participants from the National Health and Nutrition Examination Survey (NHANES) 2005-2018. Included participants had valid data on hypertension and osteoporosis, without tumors, liver diseases, gout or thyroid diseases. We explored the association between hypertension and osteoporosis by logistic regression and examined blood pressure and BMD/BMC by linear and non-linear regression. Moreover, we used machine learning models to predict the importance of various factors in the occurrence of osteoporosis and evaluated causality by mendelian randomization. Our study found that osteoporosis is significantly associated with hypertension [OR 2.072 (95% CI 2.067-2.077), p < 0.001]. After adjusting for co-variances, the association remained significant [OR 1.223 (95% CI 1.220-1.227), p < 0.001]. Our study showed that osteoporosis is positively associated with hypertension in the US population. A variety of factors influence this relationship. Specific regulatory mechanisms and confounding factors need to be further investigated.
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Affiliation(s)
- Shixuan Liu
- Department of Spine Surgery, Honghui Hospital, Xi'an Jiaotong University, Xi'an, 710054, China
| | - Shaobo Wu
- Department of Spine Surgery, Honghui Hospital, Xi'an Jiaotong University, Xi'an, 710054, China
| | - Xueyuan Bao
- Department of Infectious Diseases and Public Health, Jockey Club College of Veterinary Medicine and Life Sciences, City University of Hong Kong, Hong Kong, China
| | - Jiajia Ji
- Department of Spine Surgery, Honghui Hospital, Xi'an Jiaotong University, Xi'an, 710054, China
| | - Yuxing Ye
- Department of Spine Surgery, Honghui Hospital, Xi'an Jiaotong University, Xi'an, 710054, China
| | - Jinniu Guo
- Department of Spine Surgery, Honghui Hospital, Xi'an Jiaotong University, Xi'an, 710054, China
| | - Jiateng Liu
- Department of Spine Surgery, Honghui Hospital, Xi'an Jiaotong University, Xi'an, 710054, China
| | - Xi Wang
- Department of Spine Surgery, Honghui Hospital, Xi'an Jiaotong University, Xi'an, 710054, China
| | - Yan Zhang
- Center for Translational Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China.
| | - Dingjun Hao
- Department of Spine Surgery, Honghui Hospital, Xi'an Jiaotong University, Xi'an, 710054, China.
| | - Dageng Huang
- Department of Spine Surgery, Honghui Hospital, Xi'an Jiaotong University, Xi'an, 710054, China.
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15
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Wang T, Xi Y, Raji A, Crutchlow M, Fernandes G, Engel SS, Zhang X. Overall and subgroup prevalence of non-alcoholic fatty liver disease and prevalence of advanced fibrosis in the United States: An updated national estimate in National Health and Nutrition Examination Survey (NHANES) 2011-2018. Ann Hepatol 2024; 29:101154. [PMID: 37742743 DOI: 10.1016/j.aohep.2023.101154] [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] [Received: 04/28/2023] [Revised: 08/07/2023] [Accepted: 09/09/2023] [Indexed: 09/26/2023]
Abstract
INTRODUCTION AND OBJECTIVES Data on the prevalence of non-alcoholic fatty liver disease (NAFLD) in subgroups of the United States (US) population are limited. This study was conducted to estimate NAFLD prevalence overall and by subgroups, and prevalence of NAFLD with advanced fibrosis. MATERIALS AND METHODS Using the National Health and Nutrition Examination Survey (NHANES) 2011-2018 data, a cross-sectional study was conducted. NAFLD was defined as having a US Fatty Liver Index (USFLI) ≥ 30 in the absence of other causes of liver disease, including excessive alcohol intake, chronic hepatitis B, and chronic hepatitis C. Likelihood for having advanced fibrosis was determined by the calculated NAFLD fibrosis score (NFS; high ≥ 0.676; low < -1.445) and fibrosis-4 index (FIB-4; high ≥ 2.67; low < 1.30). RESULTS The weighted national prevalence of NAFLD in US adults was 26.7% (95% confidence interval: 25.3%-28.1%). Prevalence was higher among those aged ≥ 65 years, males, Mexican Americans, with BMI ≥ 35 kg/m2 (class 2 and 3 obesity) and with type 2 diabetes (T2D). Of those meeting the USFLI criterion for NAFLD, 18.1% and 3.7% were determined as having a high probability of advanced fibrosis based on NFS ≥ 0.676 and FIB-4 ≥ 2.67 cut-off values, respectively. CONCLUSIONS This study supports an increased prevalence of NAFLD in specific subpopulations (aged ≥ 65 years, males, Mexican Americans, obese population, and patients with T2D). The observed difference in the prevalence of advanced fibrosis as estimated by NFS and FIB-4 highlights the challenge of choosing optimal cut-off values.
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Affiliation(s)
| | - Yuzhi Xi
- University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Annaswamy Raji
- Global Clinical Development, Merck & Co., Inc., Rahway, NJ, USA
| | | | - Gail Fernandes
- Center for Observational and Real-World Evidence, Merck & Co., Inc., Rahway, NJ, USA
| | - Samuel S Engel
- Global Clinical Development, Merck & Co., Inc., Rahway, NJ, USA
| | - Xiao Zhang
- Epidemiology, Merck & Co., Inc., Rahway, NJ, USA.
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16
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Rutledge SM, Soper ER, Ma N, Pejaver V, Friedman SL, Branch AD, Kenny EE, Belbin GM, Abul-Husn NS. Association of HSD17B13 and PNPLA3 With Liver Enzymes and Fibrosis in Hispanic/Latino Individuals of Diverse Genetic Ancestries. Clin Gastroenterol Hepatol 2023; 21:2578-2587.e11. [PMID: 36610497 DOI: 10.1016/j.cgh.2022.12.025] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/09/2022] [Revised: 11/23/2022] [Accepted: 12/13/2022] [Indexed: 01/09/2023]
Abstract
BACKGROUND & AIMS Genetic variants affecting liver disease risk vary among racial and ethnic groups. Hispanics/Latinos in the United States have a high prevalence of PNPLA3 I148M, which increases liver disease risk, and a low prevalence of HSD17B13 predicted loss-of-function (pLoF) variants, which reduce risk. Less is known about the prevalence of liver disease-associated variants among Hispanic/Latino subpopulations defined by country of origin and genetic ancestry. We evaluated the prevalence of HSD17B13 pLoF variants and PNPLA3 I148M, and their associations with quantitative liver phenotypes in Hispanic/Latino participants from an electronic health record-linked biobank in New York City. METHODS This study included 8739 adult Hispanic/Latino participants of the BioMe biobank with genotyping and exome sequencing data. We estimated the prevalence of Hispanic/Latino individuals harboring HSD17B13 and PNPLA3 variants, stratified by genetic ancestry, and performed association analyses between variants and liver enzymes and Fibrosis-4 (FIB-4) scores. RESULTS Individuals with ancestry from Ecuador and Mexico had the lowest frequency of HSD17B13 pLoF variants (10%/7%) and the highest frequency of PNPLA3 I148M (54%/65%). These ancestry groups had the highest outpatient alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, and the largest proportion of individuals with a FIB-4 score greater than 2.67. HSD17B13 pLoF variants were associated with reduced ALT level (P = .002), AST level (P < .001), and FIB-4 score (P = .045). PNPLA3 I148M was associated with increased ALT level, AST level, and FIB-4 score (P < .001 for all). HSD17B13 pLoF variants mitigated the increase in ALT conferred by PNPLA3 I148M (P = .006). CONCLUSIONS Variation in HSD17B13 and PNPLA3 variants across genetic ancestry groups may contribute to differential risk for liver fibrosis among Hispanic/Latino individuals.
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Affiliation(s)
- Stephanie M Rutledge
- Division of Gastroenterology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York; Division of Liver Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Emily R Soper
- Institute for Genomic Health, Icahn School of Medicine at Mount Sinai, New York, New York; Division of Genomic Medicine, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Ning Ma
- Division of Liver Medicine, Icahn School of Medicine Mount Sinai, New York, New York
| | - Vikas Pejaver
- Institute for Genomic Health, Icahn School of Medicine at Mount Sinai, New York, New York; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Scott L Friedman
- Division of Liver Medicine, Icahn School of Medicine Mount Sinai, New York, New York
| | - Andrea D Branch
- Division of Liver Medicine, Icahn School of Medicine Mount Sinai, New York, New York
| | - Eimear E Kenny
- Institute for Genomic Health, Icahn School of Medicine at Mount Sinai, New York, New York; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York; Division of General Internal Medicine, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Gillian M Belbin
- Institute for Genomic Health, Icahn School of Medicine at Mount Sinai, New York, New York; Division of General Internal Medicine, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Noura S Abul-Husn
- Institute for Genomic Health, Icahn School of Medicine at Mount Sinai, New York, New York; Division of Genomic Medicine, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York.
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17
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Trejo MJ, Morrill KE, Klimentidis YC, Garcia DO. Examining genetic associations with hepatic steatosis in Mexican-origin adults. Ann Hepatol 2023; 28:101120. [PMID: 37271481 PMCID: PMC10486257 DOI: 10.1016/j.aohep.2023.101120] [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: 02/09/2023] [Revised: 04/24/2023] [Accepted: 05/03/2023] [Indexed: 06/06/2023]
Abstract
INTRODUCTION AND OBJECTIVES Various studies have identified single-nucleotide polymorphisms (SNPs) associated with nonalcoholic fatty liver disease (NAFLD) and related traits, including ones located in or near the LYPLAL1, GCKR, PPP1R3B, TM6SF2, MBOAT7, and PNPLA3 genes. However, these SNPs were identified primarily in populations of European ancestry. This study examined the associations of these previously identified SNPs with hepatic steatosis in a sample of Mexican-origin adults living in Southern Arizona. MATERIALS AND METHODS A total of 307 Mexican-origin adults between the ages of 18 and 64 with a body mass index (BMI) of 25 kg/m2 or higher were genotyped at the following SNPs: rs12137855 (LYPLAL1), rs1260326 (GCKR), rs4240624 (PPP1R3B), rs58542926 (TM6SF2), rs641738 (MBOAT7), and rs738409 (PNPLA3). Hepatic steatosis was assessed by transient elastography (FibroScan®) with controlled attenuation parameter. Regression models examined the association between each of the six SNPs and hepatic steatosis. BMI was examined as a potential modifier of the genetic associations. RESULTS Participants were, on average, 45 years old and mostly female (63%) with an overall mean hepatic steatosis of 288.1 dB/m. Models showed no associations between LYPLAL1, GCKR, PPP1R3B, TM6SF2, or MBOAT7 and hepatic steatosis. Only PNPLA3 was statistically significantly associated with hepatic steatosis in both unadjusted and adjusted models (p<0.01). There was no effect modification observed with BMI. CONCLUSIONS SNPs associated with NAFLD in populations of European descent did not strongly contribute to hepatic steatosis in individuals of Mexican-origin, except for rs738409 (PNPLA3). Further efforts are necessary to explore additional SNPs that may be associated with NAFLD in this high-risk population.
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Affiliation(s)
- Mario Jesus Trejo
- Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA.
| | - Kristin E Morrill
- Community & Systems Health Science Division, College of Nursing, University of Arizona, Tucson, AZ 85721, USA
| | - Yann C Klimentidis
- Department of Epidemiology and Biostatistics, Mel and Enid Zuckerman College of Public Health, University of Arizona, Tucson, AZ 85724, USA
| | - David O Garcia
- Department of Health Promotion Sciences, Mel and Enid Zuckerman College of Public Health, University of Arizona, Tucson, AZ 85724, USA
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18
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Zhang Z, Ji G, Li M. Glucokinase regulatory protein: a balancing act between glucose and lipid metabolism in NAFLD. Front Endocrinol (Lausanne) 2023; 14:1247611. [PMID: 37711901 PMCID: PMC10497960 DOI: 10.3389/fendo.2023.1247611] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/26/2023] [Accepted: 08/14/2023] [Indexed: 09/16/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a common liver disease worldwide, affected by both genetics and environment. Type 2 diabetes (T2D) stands as an independent environmental risk factor that precipitates the onset of hepatic steatosis and accelerates its progression to severe stages of liver damage. Furthermore, the coexistence of T2D and NAFLD magnifies the risk of cardiovascular disease synergistically. However, the association between genetic susceptibility and metabolic risk factors in NAFLD remains incompletely understood. The glucokinase regulator gene (GCKR), responsible for encoding the glucokinase regulatory protein (GKRP), acts as a regulator and protector of the glucose-metabolizing enzyme glucokinase (GK) in the liver. Two common variants (rs1260326 and rs780094) within the GCKR gene have been associated with a lower risk for T2D but a higher risk for NAFLD. Recent studies underscore that T2D presence significantly amplifies the effect of the GCKR gene, thereby increasing the risk of NASH and fibrosis in NAFLD patients. In this review, we focus on the critical roles of GKRP in T2D and NAFLD, drawing upon insights from genetic and biological studies. Notably, prior attempts at drug development targeting GK with glucokinase activators (GKAs) have shown potential risks of augmented plasma triglycerides or NAFLD. Conversely, overexpression of GKRP in diabetic rats improved glucose tolerance without causing NAFLD, suggesting the crucial regulatory role of GKRP in maintaining hepatic glucose and lipid metabolism balance. Collectively, this review sheds new light on the complex interaction between genes and environment in NAFLD, focusing on the GCKR gene. By integrating evidence from genetics, biology, and drug development, we reassess the therapeutic potential of targeting GK or GKRP for metabolic disease treatment. Emerging evidence suggests that selectively activating GK or enhancing GK-GKRP binding may represent a holistic strategy for restoring glucose and lipid metabolic balance.
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Affiliation(s)
| | | | - Meng Li
- Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
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19
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Morales-Romero J, Ortíz-León MC, Hernández-Gutiérrez H, Bahena-Cerón RA, Miranda-Reza A, Marín-Carmona JA, Rodríguez-Romero E, Mora SI, García-Román J, Peréz-Carreón JI, Rivadeneyra-Domínguez E, Riande-Juárez G, García-Román R. [Risk factors for metabolic dysfunction-associated fatty liver disease in the Hispanic-Mexican population.]. Rev Esp Salud Publica 2023; 97:e202306053. [PMID: 37387209 PMCID: PMC10540909] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2023] [Accepted: 05/20/2023] [Indexed: 07/01/2023] Open
Abstract
OBJECTIVE Metabolic dysfunction-associated fatty liver disease (MAFLD) is a poor attended disease, which has gained attention due the elevated number of cases in countries as Mexico, where the incidence is the number 4th globally. MAFLD develops in obese or overweighted individuals and is characterized by triglycerides accumulation in the liver, this condition can develop to hepatocellular carcinoma. It has been observed that MAFLD depends on the genetics and lifestyle. Due to the high prevalence of this disease among Hispanic population, we focused on this study in the characteristics and prevalence of MAFLD in Mexican patients. METHODS In this study were included 572 overweighted and obese patients, who underwent a screening analysis using the fatty liver index (IHG), clinical parameters were analysed, demographic and comorbidities. Frequency of variables were obtained, and the data were analysed by Chi-square test or Fisher test, odd ratio (OR) and binary logistic regression. RESULTS A MALFD prevalence of 37% were obtained, where the history of familiar obesity, paracetamol usage, carbohydrate and fat intake are shown to be risk factors. It was found that high blood pressure, central obesity and hypertriglyceridemia were also associated to the MAFLD development. On the other hand, physical exercise was a protector factor. CONCLUSIONS Our results show the necessity to study the MAFLD causalities in Mexican patients, focused on the paracetamol intake.
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Affiliation(s)
- Jaime Morales-Romero
- Instituto de Salud Pública, Universidad Veracruzana.Universidad VeracruzanaXalapa (Veracruz)Mexico
| | | | | | - Roberto A. Bahena-Cerón
- Facultad de Química Farmacéutica Biológica, Universidad Veracruzana.Universidad VeracruzanaXalapa (Veracruz)Mexico
| | - Aidé Miranda-Reza
- Facultad de Estadística e Informática, Universidad Veracruzana.Universidad VeracruzanaXalapa (Veracruz)Mexico
| | - José A. Marín-Carmona
- Facultad de Biología, Universidad Veracruzana.Universidad VeracruzanaXalapa (Veracruz)Mexico
| | - Edit Rodríguez-Romero
- Instituto de Salud Pública, Universidad Veracruzana.Universidad VeracruzanaXalapa (Veracruz)Mexico
| | - Silvia I. Mora
- Unidad de Procedimientos Preparativos y de Acceso a Servicios de Proteómica (UPASPro), Instituto de Investigaciones Biomédicas UNAM.Instituto de Investigaciones Biomédicas UNAMCiudad de México.Mexico
| | - Jonathan García-Román
- Facultad de Medicina-Región Poza Rica-Tuxpan, Universidad Veracruzana.Universidad VeracruzanaPoza Rica (Veracruz)Mexico
| | - Julio I. Peréz-Carreón
- Laboratorio de Bioquímica y Estructura de Proteínas, Instituto Nacional de Medicina Genómica.Instituto Nacional de Medicina GenómicaCiudad de México.Mexico
| | | | - Gabriel Riande-Juárez
- Instituto de Salud Pública, Universidad Veracruzana.Universidad VeracruzanaXalapa (Veracruz)Mexico
| | - Rebeca García-Román
- Instituto de Salud Pública, Universidad Veracruzana.Universidad VeracruzanaXalapa (Veracruz)Mexico
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20
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Wu N, Li J, Zhang J, Yuan F, Yu N, Zhang F, Li D, Wang J, Zhang L, Shi Y, He G, Ji G, Liu B. Waist circumference mediates the association between rs1260326 in GCKR gene and the odds of lean NAFLD. Sci Rep 2023; 13:6488. [PMID: 37081070 PMCID: PMC10119110 DOI: 10.1038/s41598-023-33753-4] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2022] [Accepted: 04/18/2023] [Indexed: 04/22/2023] Open
Abstract
While non-alcoholic fatty liver disease (NAFLD) has been widely studied, the pathophysiology of lean NAFLD, the critical NAFLD subgroup, remains elusive. This study aimed to clarify the association between polymorphisms of GCKR, waist circumference, and the odds of lean NAFLD in the elderly Chinese Han population who live in the Zhangjiang community center of Shanghai, China. Three single nucleotide polymorphisms (SNPs), including rs1260326, rs780093, and rs780094, were genotyped in MassARRAY Analyzer. The association between SNPs with waist circumference in five genetic models was analyzed and rechecked by the logistic regression analysis. Mediation models were established to evaluate whether the waist circumstance can mediate the association between SNPs and lean NAFLD. In this study, the frequency of the C allele of rs1260326, rs780093, and rs780094 was significantly lower in lean NAFLD individuals than in lean non-NAFLD ones. The association between rs1260326 in GCKR and the odds of lean NAFLD was mediated via waist circumference after adjusting gender and age in the elderly Chinese Han population (β = 1.196, R2 = 0.043, p = 0.020). For the first time, this study examined the mediating effect of waist circumference on the association between rs1260326 in GCKR and the odds of lean NAFLD (β = 0.0515, 95% CI 0.0107-0.0900, p = 0.004). It may contribute to illustrating the pathogenesis of lean NAFLD and indicate that waist circumference management might improve lean NAFLD control.
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Affiliation(s)
- Na Wu
- Shanghai Innovation Center of Traditional Chinese Medicine Health Service, School of Public Health, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Shanghai Jiao Tong University, Shanghai, 200030, China
| | - Jie Li
- Shanghai Innovation Center of Traditional Chinese Medicine Health Service, School of Public Health, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Jing Zhang
- Department of Biochemistry and Molecular Biology, Capital Medical University, Beijing, 100069, China
| | - Fan Yuan
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Shanghai Jiao Tong University, Shanghai, 200030, China
| | - Ning Yu
- Shanghai Innovation Center of Traditional Chinese Medicine Health Service, School of Public Health, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Fengwei Zhang
- Shanghai Innovation Center of Traditional Chinese Medicine Health Service, School of Public Health, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Dong Li
- Zhangjiang Community Health Service Center of Pudong New District, Shanghai, 201210, China
| | - Jianying Wang
- Shanghai Innovation Center of Traditional Chinese Medicine Health Service, School of Public Health, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Lei Zhang
- Shanghai Innovation Center of Traditional Chinese Medicine Health Service, School of Public Health, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Yi Shi
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Shanghai Jiao Tong University, Shanghai, 200030, China
| | - Guang He
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Shanghai Jiao Tong University, Shanghai, 200030, China.
| | - Guang Ji
- Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 200032, China.
| | - Baocheng Liu
- Shanghai Innovation Center of Traditional Chinese Medicine Health Service, School of Public Health, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
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21
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Cong F, Zhu L, Deng L, Xue Q, Wang J. Correlation between nonalcoholic fatty liver disease and left ventricular diastolic dysfunction in non-obese adults: a cross-sectional study. BMC Gastroenterol 2023; 23:90. [PMID: 36973654 PMCID: PMC10041784 DOI: 10.1186/s12876-023-02708-4] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/31/2022] [Accepted: 02/28/2023] [Indexed: 03/29/2023] Open
Abstract
BACKGROUND AND AIMS Non-alcoholic fatty liver disease (NAFLD) is associated with a greater risk of developing cardiovascular disease and have adverse impacts on the cardiac structure and function. Little is known about the effect of non-obese NAFLD upon cardiac function. We aimed to compare the echocardiographic parameters of left ventricle (LV) between non-obese NAFLD group and control group, and explore the correlation of non-obese NAFLD with LV diastolic dysfunction. METHODS AND RESULTS In this cross-sectional study, 316 non-obese inpatients were enrolled, including 72 participants with NAFLD (non-obese NAFLD group) and 244 participants without NAFLD (control group). LV structural and functional indices of two groups were comparatively analyzed. LV diastolic disfunction was diagnosed and graded using the ratio of the peak velocity of the early filling (E) wave to the atrial contraction (A) wave and E value. Compared with control group, the non-obese NAFLD group had the lower E/A〔(0.80 ± 0.22) vs (0.88 ± 0.35), t = 2.528, p = 0.012〕and the smaller LV end-diastolic diameter〔(4.51 ± 0.42)cm vs (4.64 ± 0.43)cm, t = 2.182, p = 0.030〕. And the non-obese NAFLD group had a higher prevalence of E/A < 1 than control group (83.3% vs 68.9%, X2 = 5.802, p = 0.016) while two groups had similar proportions of LV diastolic dysfunction (58.3% vs 53.7%, X2 = 0.484, p = 0.487). Multivariate logistic regression analysis showed that non-obese NAFLD was associated with an increase in E/A < 1 (OR = 6.562, 95%CI 2.014, 21.373, p = 0.002). CONCLUSIONS Non-obese NAFLD was associated with decrease of E/A, while more research will be necessary to evaluate risk of non-obese NAFLD for LV diastolic dysfunction in future.
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Affiliation(s)
- Fangyuan Cong
- Geriatric Department, Peking University People's Hospital, Beijing, 100044, China
| | - Luying Zhu
- Geriatric Department, Peking University People's Hospital, Beijing, 100044, China
| | - Lihua Deng
- Geriatric Department, Peking University People's Hospital, Beijing, 100044, China
| | - Qian Xue
- Geriatric Department, Peking University People's Hospital, Beijing, 100044, China
| | - Jingtong Wang
- Geriatric Department, Peking University People's Hospital, Beijing, 100044, China.
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22
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Weisman MH, Oleg Stens, Seok Kim H, Hou JK, Miller FW, Dillon CF. US Inflammatory Bowel Disease Prevalence: Surveillance Data from the U.S. National Health and Nutrition Examination Survey. Prev Med Rep 2023; 33:102173. [DOI: 10.1016/j.pmedr.2023.102173] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2022] [Revised: 03/03/2023] [Accepted: 03/06/2023] [Indexed: 03/11/2023] Open
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23
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Plasma Metabolite Signatures in Male Carriers of Genetic Variants Associated with Non-Alcoholic Fatty Liver Disease. Metabolites 2023; 13:metabo13020267. [PMID: 36837886 PMCID: PMC9964056 DOI: 10.3390/metabo13020267] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2023] [Revised: 02/01/2023] [Accepted: 02/11/2023] [Indexed: 02/16/2023] Open
Abstract
Both genetic and non-genetic factors are important in the pathophysiology of non-alcoholic fatty liver disease (NAFLD). The aim of our study was to identify novel metabolites and pathways associated with NAFLD by including both genetic and non-genetic factors in statistical analyses. We genotyped six genetic variants in the PNPLA3, TM6SF2, MBOAT7, GCKR, PPP1R3B, and HSD17B13 genes reported to be associated with NAFLD. Non-targeted metabolomic profiling was performed from plasma samples. We applied a previously validated fatty liver index to identify participants with NAFLD. First, we associated the six genetic variants with 1098 metabolites in 2 339 men without NAFLD to determine the effects of the genetic variants on metabolites, and then in 2 535 men with NAFLD to determine the joint effects of genetic variants and non-genetic factors on metabolites. We identified several novel metabolites and metabolic pathways, especially for PNPLA3, GCKR, and PPP1R38 variants relevant to the pathophysiology of NAFLD. Importantly, we showed that each genetic variant for NAFLD had a specific metabolite signature. The plasma metabolite signature was unique for each genetic variant, suggesting that several metabolites and different pathways are involved in the risk of NAFLD. The FLI index reliably identifies metabolites for NAFLD in large population-based studies.
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24
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Jia J, Zhang J, Ma D, Zhang Z, Zhao L, Wang T, Xu H. Association between healthy eating index-2015 and abdominal aortic calcification among US Adults. Front Nutr 2023; 9:1027136. [PMID: 36742001 PMCID: PMC9889545 DOI: 10.3389/fnut.2022.1027136] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2022] [Accepted: 12/28/2022] [Indexed: 01/20/2023] Open
Abstract
Aims To evaluate the relationship of the healthy eating index-2015 (HEI-2015) with abdominal aortic calcification (AAC) in US adults. Methods We conducted a cross-sectional study with data extracted from the National Health and Nutrition Examination Survey (NHANES). AAC score was measured using the scoring system of Kauppila (AAC-24) and Schousboe (AAC-8). HEI-2015, which was used for evaluating compliance with Dietary Guidelines for Americans (DGA), was calculated through two rounds of 24-h recall interviews. HEI-2015 was categorized as inadequate (<50), average (50~70), and optimal (≥70) groups for analysis, while the AAC-24 score was grouped by whether the score was >0. Weighted multiple regression analyses were conducted to estimate the association of HEI-2015 with AAC score and the presence of AAC. Moreover, smooth curve fittings, based on a generalized additive model (GAM), were applied to evaluate a possible non-linear relationship. Sensitivity analysis and subgroup analysis were performed to provide more supporting information. Results A total of 2,704 participants were included in the study (mean age, 57.61 ± 11.40 years; 51.78% were women). The mean score of HEI-2015 was 56.09 ± 13.40 (41.33 ± 6.28, 59.44 ± 5.54, and 76.90 ± 5.37 for inadequate, average, and optimal groups, respectively). After adjusting for covariates, higher HEI-2015 was associated with decreased AAC score (AAC-24: β = -0.121, 95% CI: -0.214, -0.028, P = 0.010; AAC-8: β= -0.054, 95% CI: -0.088, -0.019, P = 0.003) and lower risk of AAC (OR = 0.921, 95% CI: 0.855, 0.993, P = 0.031). Among the components of HEI-2015, a higher intake of fruits, greens, and beans was associated with a lower AAC score. Subgroup analysis showed that an inverse association of HEI-2015 with AAC score existed among different groups. Conclusion The study presented that higher HEI-2015 was related to a lower AAC score and decreased risk of having AAC, indicating that greater compliance with 2015-2020 DGA, assessed by HEI-2015, might be beneficial for preventing vascular calcification and CVD among US adults.
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Affiliation(s)
- Jundi Jia
- Graduate School, Beijing University of Chinese Medicine, Beijing, China,National Clinical Research Center for Chinese Medicine Cardiology, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Jie Zhang
- Graduate School, Beijing University of Chinese Medicine, Beijing, China,National Clinical Research Center for Chinese Medicine Cardiology, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Dan Ma
- National Clinical Research Center for Chinese Medicine Cardiology, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China,Graduate School, China Academy of Chinese Medical Sciences, Beijing, China
| | - Zihao Zhang
- Graduate School, Beijing University of Chinese Medicine, Beijing, China,National Clinical Research Center for Chinese Medicine Cardiology, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Lin Zhao
- Graduate School, Beijing University of Chinese Medicine, Beijing, China,National Clinical Research Center for Chinese Medicine Cardiology, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Tongxin Wang
- Graduate School, Beijing University of Chinese Medicine, Beijing, China,National Clinical Research Center for Chinese Medicine Cardiology, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Hao Xu
- National Clinical Research Center for Chinese Medicine Cardiology, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China,*Correspondence: Hao Xu ✉
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25
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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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26
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Josloff K, Beiriger J, Khan A, Gawel RJ, Kirby RS, Kendrick AD, Rao AK, Wang RX, Schafer MM, Pearce ME, Chauhan K, Shah YB, Marhefka GD, Halegoua-DeMarzio D. Comprehensive Review of Cardiovascular Disease Risk in Nonalcoholic Fatty Liver Disease. J Cardiovasc Dev Dis 2022; 9:419. [PMID: 36547416 PMCID: PMC9786069 DOI: 10.3390/jcdd9120419] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2022] [Revised: 11/16/2022] [Accepted: 11/23/2022] [Indexed: 11/29/2022] Open
Abstract
Nonalcoholic Fatty Liver Disease (NAFLD) is a growing global phenomenon, and its damaging effects in terms of cardiovascular disease (CVD) risk are becoming more apparent. NAFLD is estimated to affect around one quarter of the world population and is often comorbid with other metabolic disorders including diabetes mellitus, hypertension, coronary artery disease, and metabolic syndrome. In this review, we examine the current evidence describing the many ways that NAFLD itself increases CVD risk. We also discuss the emerging and complex biochemical relationship between NAFLD and its common comorbid conditions, and how they coalesce to increase CVD risk. With NAFLD's rising prevalence and deleterious effects on the cardiovascular system, a complete understanding of the disease must be undertaken, as well as effective strategies to prevent and treat its common comorbid conditions.
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Affiliation(s)
- Kevan Josloff
- Sidney Kimmel Medical College, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA
| | - Jacob Beiriger
- Sidney Kimmel Medical College, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA
| | - Adnan Khan
- Department of Internal Medicine, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA
| | - Richard J. Gawel
- Sidney Kimmel Medical College, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA
| | - Richard S. Kirby
- Sidney Kimmel Medical College, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA
| | - Aaron D. Kendrick
- Sidney Kimmel Medical College, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA
| | - Abhinav K. Rao
- Sidney Kimmel Medical College, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA
| | - Roy X. Wang
- Sidney Kimmel Medical College, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA
| | - Michelle M. Schafer
- Sidney Kimmel Medical College, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA
| | - Margaret E. Pearce
- Sidney Kimmel Medical College, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA
| | - Kashyap Chauhan
- Department of Internal Medicine, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA
| | - Yash B. Shah
- Sidney Kimmel Medical College, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA
| | - Gregary D. Marhefka
- Department of Internal Medicine, Division of Cardiology, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA
| | - Dina Halegoua-DeMarzio
- Department of Internal Medicine, Division of Gastroenterology & Hepatology, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA
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27
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Rojas YAO, Cuellar CLV, Barrón KMA, Arab JP, Miranda AL. Non-alcoholic fatty liver disease prevalence in Latin America: A systematic review and meta-analysis. Ann Hepatol 2022; 27:100706. [PMID: 35427804 DOI: 10.1016/j.aohep.2022.100706] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2022] [Revised: 03/29/2022] [Accepted: 03/30/2022] [Indexed: 02/07/2023]
Abstract
Non-alcoholic fatty liver disease (NAFLD) produces high morbidity and mortality rates. Its worldwide prevalence is 25%, but evidence from Latin America (LA) is lacking. We aimed to estimate the prevalence of NAFLD in the adult population of LA. We conducted a systematic review and meta-analysis. Data were collected from OVID, Cochrane Library and LILACS search engines. We used terms related to NAFLD and LA countries. Observational studies in adults who were born and live in LA were included. Two reviewers evaluated the articles, extracted data and assessed the risk of bias. Discrepancies were resolved by consensus or by a third reviewer. A validated tool was used to assess risk of bias. We found and analyzed 19 articles (n=5625). The prevalence in the general and captive population found was 24%. Populations with type 2 diabetes mellitus or obesity had a higher mean prevalence that reached 68%. We concluded that the average prevalence of NAFLD in LA is around 24%. Among high-risk groups, this value increases to 68%. Further studies in the general population using appropriate designs are required for an accurate estimate of the prevalence of NAFLD in LA.
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Affiliation(s)
| | | | | | - Juan Pablo Arab
- Department of Gastroenterology, School of Medicine at Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Adelina Lozano Miranda
- Liver unit, Department of Gastroenterology at Hospital Nacional Arzobispo Loayza, Lima, Peru
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28
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Zhu X, Xia M, Gao X. Update on genetics and epigenetics in metabolic associated fatty liver disease. Ther Adv Endocrinol Metab 2022; 13:20420188221132138. [PMID: 36325500 PMCID: PMC9619279 DOI: 10.1177/20420188221132138] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/09/2022] [Accepted: 09/25/2022] [Indexed: 11/06/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is becoming the most frequent chronic liver disease worldwide. Metabolic (dysfunction) associated fatty liver disease (MAFLD) is suggested to replace the nomenclature of NAFLD. For individuals with metabolic dysfunction, multiple NAFLD-related factors also contribute to the development and progression of MAFLD including genetics and epigenetics. The application of genome-wide association study (GWAS) and exome-wide association study (EWAS) uncovers single-nucleotide polymorphisms (SNPs) in MAFLD. In addition to the classic SNPs in PNPLA3, TM6SF2, and GCKR, some new SNPs have been found recently to contribute to the pathogenesis of liver steatosis. Epigenetic factors involving DNA methylation, histone modifications, non-coding RNAs regulations, and RNA methylation also play a critical role in MAFLD. DNA methylation is the most reported epigenetic modification. Developing a non-invasion biomarker to distinguish metabolic steatohepatitis (MASH) or liver fibrosis is ongoing. In this review, we summarized and discussed the latest progress in genetic and epigenetic factors of NAFLD/MAFLD, in order to provide potential clues for MAFLD treatment.
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Affiliation(s)
- Xiaopeng Zhu
- Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan Institute for Metabolic Diseases, Fudan University, Shanghai, China
| | - Mingfeng Xia
- Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan Institute for Metabolic Diseases, Fudan University, 180 Fenglin Rd, Shanghai 200032, China
| | - Xin Gao
- Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan Institute for Metabolic Diseases, Fudan University, Shanghai, China
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29
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Kimura M, Iguchi T, Iwasawa K, Dunn A, Thompson WL, Yoneyama Y, Chaturvedi P, Zorn AM, Wintzinger M, Quattrocelli M, Watanabe-Chailland M, Zhu G, Fujimoto M, Kumbaji M, Kodaka A, Gindin Y, Chung C, Myers RP, Subramanian GM, Hwa V, Takebe T. En masse organoid phenotyping informs metabolic-associated genetic susceptibility to NASH. Cell 2022; 185:4216-4232.e16. [PMID: 36240780 PMCID: PMC9617783 DOI: 10.1016/j.cell.2022.09.031] [Citation(s) in RCA: 63] [Impact Index Per Article: 21.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2022] [Revised: 08/01/2022] [Accepted: 09/23/2022] [Indexed: 11/07/2022]
Abstract
Genotype-phenotype associations for common diseases are often compounded by pleiotropy and metabolic state. Here, we devised a pooled human organoid-panel of steatohepatitis to investigate the impact of metabolic status on genotype-phenotype association. En masse population-based phenotypic analysis under insulin insensitive conditions predicted key non-alcoholic steatohepatitis (NASH)-genetic factors including the glucokinase regulatory protein (GCKR)-rs1260326:C>T. Analysis of NASH clinical cohorts revealed that GCKR-rs1260326-T allele elevates disease severity only under diabetic state but protects from fibrosis under non-diabetic states. Transcriptomic, metabolomic, and pharmacological analyses indicate significant mitochondrial dysfunction incurred by GCKR-rs1260326, which was not reversed with metformin. Uncoupling oxidative mechanisms mitigated mitochondrial dysfunction and permitted adaptation to increased fatty acid supply while protecting against oxidant stress, forming a basis for future therapeutic approaches for diabetic NASH. Thus, "in-a-dish" genotype-phenotype association strategies disentangle the opposing roles of metabolic-associated gene variant functions and offer a rich mechanistic, diagnostic, and therapeutic inference toolbox toward precision hepatology. VIDEO ABSTRACT.
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Affiliation(s)
- Masaki Kimura
- Division of Gastroenterology, Hepatology and Nutrition, Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA
| | - Takuma Iguchi
- Division of Gastroenterology, Hepatology and Nutrition, Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA
| | - Kentaro Iwasawa
- Division of Gastroenterology, Hepatology and Nutrition, Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA
| | - Andrew Dunn
- Division of Gastroenterology, Hepatology and Nutrition, Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA
| | - Wendy L Thompson
- Division of Gastroenterology, Hepatology and Nutrition, Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA
| | - Yosuke Yoneyama
- Institute of Research, Tokyo Medical and Dental University (TMDU), Tokyo 113-8510, Japan
| | - Praneet Chaturvedi
- Division of Gastroenterology, Hepatology and Nutrition, Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA; Center for Stem Cell and Organoid Medicine (CuSTOM), Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA
| | - Aaron M Zorn
- Division of Gastroenterology, Hepatology and Nutrition, Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA; Center for Stem Cell and Organoid Medicine (CuSTOM), Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA
| | - Michelle Wintzinger
- Division of Molecular Cardiovascular Biology, Heart Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA
| | - Mattia Quattrocelli
- Division of Molecular Cardiovascular Biology, Heart Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA
| | - Miki Watanabe-Chailland
- NMR-Based Metabolomics Core Facility, Division of Pathology and Laboratory Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA
| | - Gaohui Zhu
- Division of Endocrinology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA
| | - Masanobu Fujimoto
- Division of Endocrinology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA
| | - Meenasri Kumbaji
- Division of Endocrinology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA
| | - Asuka Kodaka
- Communication Design Center, Advanced Medical Research Center, Yokohama City University, Yokohama 236-0004, Japan
| | | | | | - Robert P Myers
- Gilead Sciences, Foster City, CA 94404, USA; The Liver Company, Inc., Palo Alto, CA 94303, USA
| | - G Mani Subramanian
- Gilead Sciences, Foster City, CA 94404, USA; The Liver Company, Inc., Palo Alto, CA 94303, USA
| | - Vivian Hwa
- Center for Stem Cell and Organoid Medicine (CuSTOM), Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA; Division of Endocrinology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA
| | - Takanori Takebe
- Division of Gastroenterology, Hepatology and Nutrition, Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA; Institute of Research, Tokyo Medical and Dental University (TMDU), Tokyo 113-8510, Japan; Center for Stem Cell and Organoid Medicine (CuSTOM), Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA; Communication Design Center, Advanced Medical Research Center, Yokohama City University, Yokohama 236-0004, Japan.
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30
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Kubiliun MJ, Cohen JC, Hobbs HH, Kozlitina J. Contribution of a genetic risk score to ethnic differences in fatty liver disease. Liver Int 2022; 42:2227-2236. [PMID: 35620859 PMCID: PMC9427702 DOI: 10.1111/liv.15322] [Citation(s) in RCA: 32] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2022] [Revised: 05/23/2022] [Accepted: 05/25/2022] [Indexed: 01/01/2023]
Abstract
BACKGROUND AND AIMS Susceptibility to fatty liver disease (FLD) varies among individuals and between racial/ethnic groups. Several genetic variants influence FLD risk, but whether these variants explain racial/ethnic differences in FLD prevalence is unclear. We examined the contribution of genetic risk factors to racial/ethnic-specific differences in FLD. METHODS A case-control study comparing FLD patients (n = 1194) and population-based controls (n = 3120) was performed. Patient characteristics, FLD risk variants (PNPLA3-rs738409 + rs6006460, TM6SF2-rs58542926, HSD17B13-rs80182459 + rs72613567, MBOAT7/TMC4-rs641738, and GCKR-rs1260326) and a multi-locus genetic risk score (GRS) were examined. The odds of FLD for individuals with different risk factor burdens were determined. RESULTS Hispanics and Whites were over-represented (56% vs. 38% and 36% vs. 29% respectively) and Blacks under-represented (5% vs. 23%) among FLD patients, compared to the population from which controls were selected (p < .001). Among cases and controls, Blacks had a lower and Hispanics a greater, net number of risk alleles than Whites (p < .001). GRS was associated with increased odds of FLD (ORQ5vsQ1 = 8.72 [95% CI = 5.97-13.0], p = 9.8 × 10-28 ), with the association being stronger in Hispanics (ORQ5vsQ1 = 14.8 [8.3-27.1]) than Blacks (ORQ5vsQ1 = 3.7 [1.5-11.5], P-interaction = 0.002). After accounting for GRS, the odds of FLD between Hispanics and Whites did not differ significantly (OR = 1.06 [0.87-1.28], p = .58), whereas Blacks retained much lower odds of FLD (OR = 0.21, [0.15-0.30], p < .001). CONCLUSIONS Blacks had a lower and Hispanics a greater FLD risk allele burden than Whites. These differences contributed to, but did not fully explain, racial/ethnic differences in FLD prevalence. Identification of additional factors protecting Blacks from FLD may provide new targets for prevention and treatment of FLD.
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Affiliation(s)
- Maddie J. Kubiliun
- Division of Digestive and Liver Diseases, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA
| | - Jonathan C. Cohen
- The Center for Human Nutrition, University of Texas Southwestern Medical Center, Dallas, Texas, USA,The Eugene McDermott Center of Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, Texas, USA,Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA
| | - Helen H. Hobbs
- The Eugene McDermott Center of Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, Texas, USA,Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA,Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, Texas, USA,Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, Texas, USA
| | - Julia Kozlitina
- The Eugene McDermott Center of Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, Texas, USA,Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA,Department of Population and Data Sciences, University of Texas Southwestern Medical Center, Dallas, Texas, USA
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The development of the Metabolic-associated Fatty Liver Disease during pharmacotherapy of mental disorders - a review. CURRENT PROBLEMS OF PSYCHIATRY 2022. [DOI: 10.2478/cpp-2022-0013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Abstract
Introduction: Metabolic-associated Fatty Liver Disease (MAFLD) is a term for Non-alcoholic Fatty Liver Disease (NAFLD) that highlights its association with components of the Metabolic Syndrome (MetS). MAFLD is becoming a clinically significant problem due to its increasing role in the pathogenesis of cryptogenic cirrhosis of the liver.
Material and methods: The resulting work is a review of the most important information on the risk of MAFLD development in the context of the use of particular groups of psychotropic drugs. The study presents the epidemiology, with particular emphasis on the population of psychiatric patients, pathophysiology and scientific reports analyzing the effect of the psychotropic medications on MAFLD development.
Results: The drugs that can have the greatest impact on the development of MAFLD are atypical antipsychotics, especially olanzapine, and mood stabilizers (MS) - valproic acid (VPA). Their effect is indirect, mainly through dysregulation of organism’s carbohydrate and lipid metabolism.
Conclusions: The population of psychiatric patients is particularly vulnerable to the development of MAFLD. At the root of this disorder lies the specificity of mental disorders, improper dietary habits, low level of physical activity and tendency to addictions. Also, the negative impact of the psychotropic drugs on the systemic metabolism indirectly contributes to the development of MAFLD. In order to prevent fatty liver disease, it is necessary to monitor metabolic and liver parameters regularly, and patients should be screened by ultrasound examination of the liver. There are also important preventive actions from the medical professionals, including education of patients and sensitizing to healthy lifestyle.
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Jones GS, Graubard BI, Alvarez CS, McGlynn KA. Prediction of nonalcoholic fatty liver disease using anthropometry and body fat measures by sex and race/ethnicity in the United States. Obesity (Silver Spring) 2022; 30:1760-1765. [PMID: 35945693 DOI: 10.1002/oby.23514] [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: 04/07/2022] [Revised: 05/18/2022] [Accepted: 06/09/2022] [Indexed: 11/07/2022]
Abstract
OBJECTIVE The prevalence of nonalcoholic fatty liver disease (NAFLD) is increasing in the United States and is strongly linked to obesity in many, but not all, racial/ethnic groups. It is conceivable that the lack of correspondence is related to differential fat distribution. The study objective was to examine which fat distribution measures best predicted NAFLD by sex within racial/ethnic groups. METHODS The analysis included 1,404 participants from the 2017-2018 National Health and Nutrition Examination Survey (NHANES). Area under the receiver operating characteristic curve (AUC) analyses compared the ability of dual-energy x-ray absorptiometry-measured percentage total fat and abdominal fat with measured BMI, waist circumference, and waist to height ratio to predict ultrasound transient-elastography-assessed NAFLD in each sex and racial/ethnic group. RESULTS AUC analysis found the best predictors of NAFLD among men were waist circumference and total abdominal fat area (AUC: 84.1%) and the best predictor among women was visceral fat (AUC: 85.2). NAFLD prediction by body fat measures, however, was similar between racial/ethnic groups. CONCLUSIONS The best predictors of NAFLD, using body fat distribution measures, vary by sex but not by racial/ethnic group.
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Affiliation(s)
- Gieira S Jones
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland, USA
| | - Barry I Graubard
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland, USA
| | - Christian S Alvarez
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland, USA
| | - Katherine A McGlynn
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland, USA
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Liao S, An K, Liu Z, He H, An Z, Su Q, Li S. Genetic variants associated with metabolic dysfunction-associated fatty liver disease in western China. J Clin Lab Anal 2022; 36:e24626. [PMID: 35881683 PMCID: PMC9459258 DOI: 10.1002/jcla.24626] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2022] [Revised: 06/21/2022] [Accepted: 07/13/2022] [Indexed: 02/05/2023] Open
Abstract
INTRODUCTION We aimed to confirm the association between some single nucleotide polymorphisms (SNPs) and metabolic dysfunction-associated fatty liver disease (MAFLD) in western China. METHODS A total of 286 cases and 250 healthy controls were enrolled in our study. All samples were genotyped for patatin-like phospholipase domain containing 3 (PNPLA3) rs738409, transmembrane 6 superfamily member 2 (TM6SF2) rs58542926, membrane-bound O-acyltransferase domain containing 7 (MBOAT7) rs641738, glucokinase regulator (GCKR) rs1260326 and rs780094, and GATA zinc finger domain containing 2A (GATAD2A) rs4808199. Using logistic regression analysis, we evaluated the association between MAFLD and each SNP under different models. Multiple linear regression was used to find the association between SNPs and laboratory characteristics. Multifactor dimensionality reduction was applied to test SNP-SNP interactions. RESULTS The recessive model and additive model of PNPLA3 rs738409 variant were related to MAFLD (odds ratio [OR] = 1.791 and 1.377, respectively, p = 0.038 and 0.027, respectively). However, after Benjamini-Hochberg adjustment for multiple tests, all associations were no longer statistically significant. PNPLA3 rs738409 correlated with AST levels. GCKR rs780094 and rs1260326 negatively correlated with serum glucose but positively correlated with triglycerides in MAFLD. Based on MDR analysis, the best single-locus and multilocus models for MAFLD risk were rs738409 and six-locus models, respectively. CONCLUSIONS In the Han population in western China, no association was found between these SNPs and the risk of MAFLD. PNPLA3 rs738409 was associated with aspartate aminotransferase levels in MAFLD patients. GCKR variants were associated with increased triglyceride levels and reduced serum fasting glucose in patients with MAFLD.
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Affiliation(s)
- Shenling Liao
- Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, China
| | - Kang An
- Department of General Practice, West China Hospital, Sichuan University, Chengdu, China
| | - Zhi Liu
- Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, China
| | - He He
- Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, China
| | - Zhenmei An
- Department of Endocrinology and Metabolism, West China Hospital, Sichuan University, Chengdu, China
| | - Qiaoli Su
- Department of General Practice, West China Hospital, Sichuan University, Chengdu, China
| | - Shuangqing Li
- Department of General Practice, West China Hospital, Sichuan University, Chengdu, China
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Lazo M, Xie J, Alvarez CS, Parisi D, Yang S, Rivera-Andrade A, Kroker-Lobos MF, Groopman JD, Guallar E, Ramirez-Zea M, Arking DE, McGlynn KA. Frequency of the PNPLA3 rs738409 polymorphism and other genetic loci for liver disease in a Guatemalan adult population. Liver Int 2022; 42:1470-1474. [PMID: 35365950 PMCID: PMC9241623 DOI: 10.1111/liv.15268] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/12/2022] [Accepted: 03/31/2022] [Indexed: 02/13/2023]
Affiliation(s)
- Mariana Lazo
- Department of Community Health and Prevention, Drexel Dornsife School of Public Health, Philadelphia, PA, 19104, USA,Urban Health Collaborative, Drexel Dornsife School of Public Health, Philadelphia, PA,Division of General Internal Medicine, School of Medicine, Johns Hopkins University, Baltimore, MD, 21205, USA
| | - Jiaqi Xie
- Department of Genetic Medicine, School of Medicine, Johns Hopkins University, Baltimore, MD 21205, USA
| | - Christian S. Alvarez
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD 20850, USA
| | | | - Stephanie Yang
- Department of Genetic Medicine, School of Medicine, Johns Hopkins University, Baltimore, MD 21205, USA
| | - Alvaro Rivera-Andrade
- INCAP Research Center for the Prevention of Chronic Diseases, Institute of Nutrition of Central America and Panama, Guatemala City, Guatemala
| | - Maria F. Kroker-Lobos
- INCAP Research Center for the Prevention of Chronic Diseases, Institute of Nutrition of Central America and Panama, Guatemala City, Guatemala
| | - John D. Groopman
- Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205
| | - Eliseo Guallar
- Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205
| | - Manuel Ramirez-Zea
- INCAP Research Center for the Prevention of Chronic Diseases, Institute of Nutrition of Central America and Panama, Guatemala City, Guatemala
| | - Dan E. Arking
- Department of Genetic Medicine, School of Medicine, Johns Hopkins University, Baltimore, MD 21205, USA
| | - Katherine A. McGlynn
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD 20850, USA
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Morales-Arráez D, Ventura-Cots M, Altamirano J, Abraldes JG, Cruz-Lemini M, Thursz MR, Atkinson SR, Sarin SK, Kim W, Chavez-Araujo R, Higuera-de la Tijera MF, Singal AK, Shah VH, Kamath PS, Duarte-Rojo A, Charles EA, Vargas V, Jager M, Rautou PE, Rincon D, Zamarripa F, Restrepo-Gutiérrez JC, Torre A, Lucey MR, Arab JP, Mathurin P, Louvet A, García-Tsao G, González JA, Verna EC, Brown RS, Argemi J, Fernández-Carrillo C, Clemente A, Alvarado-Tapias E, Forrest E, Allison M, Bataller R. The MELD Score Is Superior to the Maddrey Discriminant Function Score to Predict Short-Term Mortality in Alcohol-Associated Hepatitis: A Global Study. Am J Gastroenterol 2022; 117:301-310. [PMID: 34962498 PMCID: PMC8999152 DOI: 10.14309/ajg.0000000000001596] [Citation(s) in RCA: 52] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/06/2021] [Accepted: 10/27/2021] [Indexed: 02/03/2023]
Abstract
INTRODUCTION Several scoring systems predict mortality in alcohol-associated hepatitis (AH), including the Maddrey discriminant function (mDF) and model for end-stage liver disease (MELD) score developed in the United States, Glasgow alcoholic hepatitis score in the United Kingdom, and age, bilirubin, international normalized ratio, and creatinine score in Spain. To date, no global studies have examined the utility of these scores, nor has the MELD-sodium been evaluated for outcome prediction in AH. In this study, we assessed the accuracy of different scores to predict short-term mortality in AH and investigated additional factors to improve mortality prediction. METHODS Patients admitted to hospital with a definite or probable AH were recruited by 85 tertiary centers in 11 countries and across 3 continents. Baseline demographic and laboratory variables were obtained. The primary outcome was all-cause mortality at 28 and 90 days. RESULTS In total, 3,101 patients were eligible for inclusion. After exclusions (n = 520), 2,581 patients were enrolled (74.4% male, median age 48 years, interquartile range 40.9-55.0 years). The median MELD score was 23.5 (interquartile range 20.5-27.8). Mortality at 28 and 90 days was 20% and 30.9%, respectively. The area under the receiver operating characteristic curve for 28-day mortality ranged from 0.776 for MELD-sodium to 0.701 for mDF, and for 90-day mortality, it ranged from 0.773 for MELD to 0.709 for mDF. The area under the receiver operating characteristic curve for mDF to predict death was significantly lower than all other scores. Age added to MELD obtained only a small improvement of AUC. DISCUSSION These results suggest that the mDF score should no longer be used to assess AH's prognosis. The MELD score has the best performance in predicting short-term mortality.
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Affiliation(s)
- D Morales-Arráez
- Division of Gastroenterology, Hepatology and Nutrition, Pittsburgh Liver Research Center, University of Pittsburgh Medical Center (UPMC), Pittsburgh, Pennsylvania, USA
- Department of Gastroenterology and Hepatology, Hospital Universitario de Canarias, Canarias, Spain
| | - M Ventura-Cots
- Division of Gastroenterology, Hepatology and Nutrition, Pittsburgh Liver Research Center, University of Pittsburgh Medical Center (UPMC), Pittsburgh, Pennsylvania, USA
| | - J Altamirano
- Department of Internal Medicine, Hospital Quironsalud, Barcelona, Spain
| | - J G Abraldes
- Division of Gastroenterology, Liver Unit, University of Alberta, Edmonton, Canada
| | - M Cruz-Lemini
- Women and Perinatal Research Group, Obstetrics and Gynecology Department, Sant Pau University Hospital, Barcelona, Spain, and Maternal and Child Health and Development Network (SAMID, RD16/0022/0015), Instituto de Salud Carlos III, Spanish Ministry of Health, Spain
| | - M R Thursz
- Department of Metabolism, Digestive disease and Reproduction, Imperial College London, UK
| | - S R Atkinson
- Division of Gastroenterology, Hepatology and Nutrition, Pittsburgh Liver Research Center, University of Pittsburgh Medical Center (UPMC), Pittsburgh, Pennsylvania, USA
- Department of Metabolism, Digestive disease and Reproduction, Imperial College London, UK
| | - S K Sarin
- Department of Hepatology, Institute of Liver & Biliary Sciences, New Delhi, India
| | - W Kim
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Seoul Metropolitan Government Seoul National University Boramae Medical Center, Seoul National University College of Medicine, Seoul, Korea
| | - R Chavez-Araujo
- Hospital das Clinicas, Faculty of Medicine, University of São Paulo, São Paulo, Brazil
| | | | - A K Singal
- Division of Gastroenterology and Hepatology, the University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - V H Shah
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
| | - P S Kamath
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
| | - A Duarte-Rojo
- Division of Gastroenterology and Hepatology, Department of Medicine, the University of Arkansas for Medical Science, Little Rock, Arkansas, USA
| | - E A Charles
- Division of Gastroenterology, Hepatology and Nutrition, Pittsburgh Liver Research Center, University of Pittsburgh Medical Center (UPMC), Pittsburgh, Pennsylvania, USA
| | - V Vargas
- Liver Unit, Department of Internal Medicine, Hospital Universitari Vall d'Hebron, Universidad Autónoma, Barcelona, CIBERehd, Barcelona, Spain
| | - M Jager
- Service d'Hépatologie, Centre de Référence des Maladies Vasculaires du Foie, DHU Unity, Pôle des Maladies de l'Appareil Digestif, Hôpital Beaujon, AP-HP, Clichy, France
| | - P E Rautou
- Service d'Hépatologie, Centre de Référence des Maladies Vasculaires du Foie, DHU Unity, Pôle des Maladies de l'Appareil Digestif, Hôpital Beaujon, AP-HP, Clichy, France
- Inserm, UMR-970, Paris Cardiovascular Research Center, PARCC, Paris, France
| | - D Rincon
- Hepatology Department, Hospital General Universitario Gregorio Marañón, CIBERehd and Universidad Complutense, Madrid, Spain
| | - F Zamarripa
- Gastroenterology, Juarez Hospital, Mexico City, Mexico
| | - J C Restrepo-Gutiérrez
- Liver Transplant Program, Hospital Pablo Tobon Uribe, University of Antioquia, Medellin, Colombia
| | - A Torre
- Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran, Mexico City, Mexico
| | - M R Lucey
- Division of Gastroenterology and Hepatology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA
| | - J P Arab
- Departamento de Gastroenterología, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - P Mathurin
- Service des Maladies de l'Appareil Digestif et de la Nutrition, CHU Lille, Lille, France
- LIRIC-Lille Inflammation Research International Center-U995, Univ. Lille, Inserm, CHU Lille, Lille, France
| | - A Louvet
- Service des Maladies de l'Appareil Digestif et de la Nutrition, CHU Lille, Lille, France
| | - G García-Tsao
- Section of Digestive Diseases, Yale University School of Medicine/VA-CT Healthcare System, New Haven/West Haven, Connecticut¸ USA
| | - J A González
- Gastroenterology Department, Hospital Universitario "Dr. José E González" Universidad Autónoma de Nuevo León, Monterrey, Mexico
| | - E C Verna
- Division of Digestive and Liver Diseases, Department of Medicine and Center for Liver Disease and Transplantation, Columbia University Irving Medical Center, New York, New York, USA
| | - R S Brown
- Division of Gastroenterology and Hepatology, Weill Cornell Medical College, New York, New York, USA
| | - J Argemi
- Division of Gastroenterology, Hepatology and Nutrition, Pittsburgh Liver Research Center, University of Pittsburgh Medical Center (UPMC), Pittsburgh, Pennsylvania, USA
- Liver Unit, Clinica Universidad de Navarra, IdisNA. Pamplona, Spain
| | - C Fernández-Carrillo
- Division of Gastroenterology, Hepatology and Nutrition, Pittsburgh Liver Research Center, University of Pittsburgh Medical Center (UPMC), Pittsburgh, Pennsylvania, USA
| | - A Clemente
- Division of Gastroenterology, Hepatology and Nutrition, Pittsburgh Liver Research Center, University of Pittsburgh Medical Center (UPMC), Pittsburgh, Pennsylvania, USA
- Liver Unit and Digestive Department H.G.U. Gregorio Marañón, Madrid, Spain
- CIBERehd, Instituto de Salud Carlos III, Madrid, Spain
| | - E Alvarado-Tapias
- Division of Gastroenterology, Hepatology and Nutrition, Pittsburgh Liver Research Center, University of Pittsburgh Medical Center (UPMC), Pittsburgh, Pennsylvania, USA
| | - E Forrest
- Glasgow Royal Infirmary, Glasgow, UK
| | - M Allison
- Liver Unit, Cambridge Biomedical Research Centre, Cambridge, UK
| | - R Bataller
- Division of Gastroenterology, Hepatology and Nutrition, Pittsburgh Liver Research Center, University of Pittsburgh Medical Center (UPMC), Pittsburgh, Pennsylvania, USA
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Zhou D, Liu X, Lo K, Huang Y, Feng Y. The effect of total cholesterol/high-density lipoprotein cholesterol ratio on mortality risk in the general population. Front Endocrinol (Lausanne) 2022; 13:1012383. [PMID: 36589799 PMCID: PMC9797665 DOI: 10.3389/fendo.2022.1012383] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/05/2022] [Accepted: 11/24/2022] [Indexed: 12/16/2022] Open
Abstract
BACKGROUND The relationship between the total cholesterol/high-density lipoprotein cholesterol (TC/HDL-C) ratio and all-cause and cardiovascular mortality has not been elucidated. Herein, we intend to probe the effect of the TC/HDL-C ratio on all-cause and cardiovascular mortality in the general population. METHODS From the 1999-2014 National Health and Nutrition Examination Surveys (NHANES), a total of 32,405 health participants aged ≥18 years were included. The TC/HDL-C levels were divided into five groups: Q1: <2.86, Q2: 2.86-3.46, Q3: 3.46-4.12, Q4: 4.12-5.07, Q5: >5.07. Multivariate Cox regression models were used to explore the relationship between the TC/HDL-C ratio and cardiovascular and all-cause mortality. Two-piecewise linear regression models and restricted cubic spline regression were used to explore nonlinear and irregularly shaped relationships. Kaplan-Meier survival curve and subgroup analyses were conducted. RESULTS The population comprised 15,675 men and 16,730 women with a mean age of 43 years. During a median follow-up of 98 months (8.1 years), 2,859 mortality cases were recorded. The TC/HDL-C ratio and all-cause mortality showed a nonlinear association after adjusting for confounding variables in the restricted cubic spline analysis. Hazard ratios (HRs) of all-cause mortality were particularly positively related to the level of TC/HDL-C ratio in the higher range >5.07 and in the lower range <2.86 (HR 1.26; 95% CI 1.10, 1.45; HR 1.18; 95% CI 1.00, 1.38, respectively), although the HRs of cardiovascular disease mortality showed no difference among the five groups. In the two-piecewise linear regression model, a TC/HDL-C ratio range of ≥4.22 was positively correlated with cardiovascular mortality (HR 1.13; 95% CI 1.02, 1.25). In the subgroup analysis, a nonlinear association between TC/HDL-C and all-cause mortality was found in those aged <65 years, men, and the no lipid drug treatment population. CONCLUSION A nonlinear association between the TC/HDL-C ratio and all-cause mortality was found, indicating that a too-low or too-high TC/HDL-C ratio might increase all-cause mortality. However, for cardiovascular mortality, it does not seem so. The cutoff value was 4.22. The individuals had higher cardiovascular mortality with a TC/HDL-C ratio >4.22.
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Affiliation(s)
- Dan Zhou
- Department of Cardiology, Guangdong Cardiovascular Institute, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Xiaocong Liu
- Department of Cardiology, Guangdong Cardiovascular Institute, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Kenneth Lo
- Department of Cardiology, Guangdong Cardiovascular Institute, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
- Department of Epidemiology, Centre for Global Cardio-Metabolic Health, Brown University, Providence, RI, United States
- Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hong Kong, Hong Kong SAR, China
| | - Yuqing Huang
- Department of Cardiology, Guangdong Cardiovascular Institute, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Yingqing Feng
- Department of Cardiology, Guangdong Cardiovascular Institute, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
- *Correspondence: Yingqing Feng,
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Lazo M, Bilal U, Mitchell MC, Potter J, Hernaez R, Clark JM. Interaction Between Alcohol Consumption and PNPLA3 Variant in the Prevalence of Hepatic Steatosis in the US Population. Clin Gastroenterol Hepatol 2021; 19:2606-2614.e4. [PMID: 32882427 PMCID: PMC7914282 DOI: 10.1016/j.cgh.2020.08.054] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/29/2020] [Revised: 08/13/2020] [Accepted: 08/25/2020] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS To our knowledge, the interaction between alcohol consumption and PNPLA3 genotype on hepatic steatosis has not been explored in a representative sample. To examine the interaction between alcohol consumption and PNPLA3 genotype on hepatic steatosis in the US adult population. METHODS Cross-sectional study of 4,674 adult participants of the Third National Health and Nutrition Examination Survey, Phase 2 (1991-1994) with data on PNPLA3 genotype, self-reported alcohol consumption, ultrasound-defined hepatic steatosis and socio-demographic characteristics. RESULTS In 1991-1994 in the U.S. population, the weighted allele frequency of the G (risk) allele of the rs738409 at PNPLA3 was 25.4%. We confirmed both a J shaped association between alcohol consumption and hepatic steatosis among those with the CC genotype of PNPLA3, and a higher prevalence of hepatic steatosis among those with PNPLA3 gene G variant. We found evidence of an interaction of PNPLA3 G allele presence on the association between moderate alcohol consumption and hepatic steatosis on both the multiplicative (relative prevalence ratio [RPR]=1.95, 95% confidence interval [CI] 1.04-3.65) and additive scales (relative excess risk due to interaction=0.49, 95% CI 0.13-0.85). Compared to never drinkers, moderate alcohol drinking was associated with a 48% decreased risk of hepatic steatosis only among those without PNPLA3 G allele (PR=0.52, 95% CI 0.26-1.05), with no association among those with at least one copy of the PNPLA3 G allele (PR=1.02, 95% CI 0.68-1.54). CONCLUSIONS Our results suggest that a highly common and strong genetic susceptibility to liver disease is modifiable by the level of alcohol consumption. Keeping alcohol consumption low may offset genetic predisposition to liver disease.
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Affiliation(s)
- Mariana Lazo
- Department of Community Health and Prevention, Dornsife School of Public Health, Drexel University, Philadelphia, Pennsylvania; Urban Health Collaborative, Dornsife School of Public Health, Drexel University, Philadelphia, Pennsylvania; Division of General Internal Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland.
| | - Usama Bilal
- Urban Health Collaborative, Dornsife School of Public Health, Drexel University, Philadelphia, PA, USA,Department of Epidemiology and Biostatistics, Dornsife School of Public Health, Drexel University, Philadelphia, PA, USA
| | - Mack C. Mitchell
- Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas
| | - James Potter
- Division of Gastroenterology & Hepatology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Ruben Hernaez
- Section of Gastroenterology, Michael E. DeBakey Veterans Affairs Medical Center, Houston, TX Center, Houston, TX, USA; Center for Innovations in Quality, Effectiveness and Safety (IQuESt), Michael E. DeBakey Veterans Affairs Medical Center, Houston, TX, USA; Section of Gastroenterology and Hepatology, Department of Medicine, Baylor College of Medicine, Houston, TX, USA
| | - Jeanne M. Clark
- Division of General Internal Medicine, School of Medicine, Johns Hopkins University, Baltimore, MD, USA,Division of Gastroenterology & Hepatology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
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Correlations between PNPLA3 Gene Polymorphisms and NAFLD in Type 2 Diabetic Patients. MEDICINA (KAUNAS, LITHUANIA) 2021; 57:medicina57111249. [PMID: 34833467 PMCID: PMC8620174 DOI: 10.3390/medicina57111249] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/19/2021] [Revised: 11/03/2021] [Accepted: 11/12/2021] [Indexed: 12/20/2022]
Abstract
Background and Objectives: Non-alcoholic fatty liver disease is a worldwide significant public health problem, particularly in patients with type 2 diabetes mellitus. Identifying possible risk factors for the disease is mandatory for a better understandingand management of this condition. Patatin-like phospholipase domain-containing protein 3 (PNPLA3) has been linked to the development and evolution of fatty liver but not to insulin resistance. The aim of this study isto evaluate the relationships between PNPLA3 and fatty liver, metabolic syndrome and subclinical atherosclerosis. Materials and Methods: The study group consisted of patients with type 2 diabetes mellitus without insulin treatment. The degree of liver fat loading was assessed by ultrasonography, and subclinical atherosclerosis was assessed using carotid intima-media thickness (CIMT). PNPLA3 rs738409 genotype determination was performed by high-resolution melting analysis that allowed three standard genotypes: CC, CG, and GG. Results: Among the 92 patients, more than 90% showed various degrees of hepatic steatosis, almost 62% presented values over the normal limit for the CIMT. The majority of the included subjects met the criteria for metabolic syndrome. Genotyping of PNPLA3 in 68 patients showed that the difference between subjects without steatosis and subjects with hepatic steatosis was due to the higher frequency of genotype GG. The CC genotype was the most common in the group we studied and was significantly more frequent in the group of subjects with severe steatosis; the GG genotype was significantly more frequent in subjects with moderate steatosis; the frequency of the CG genotype was not significantly different among the groups.When we divided the group of subjects into two groups: those with no or mild steatosis and those with moderate or severe steatosis it was shown that the frequency of the GG genotype was significantly higher in the group of subjects with moderate or severe steatosis. PNPLA3 genotypes were not associated with metabolic syndrome, subclinical atherosclerosis, or insulin resistance. Conclusions: Our results suggest that PNPLA3 does not independently influence cardiovascular risk in patients with type 2 diabetes mellitus. The hypothesis that PNPLA3 may have a cardioprotective effect requires future confirmation.
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Alqahtani SA, Paik JM, Biswas R, Arshad T, Henry L, Younossi ZM. Poor Awareness of Liver Disease Among Adults With NAFLD in the United States. Hepatol Commun 2021; 5:1833-1847. [PMID: 34558829 PMCID: PMC8557315 DOI: 10.1002/hep4.1765] [Citation(s) in RCA: 83] [Impact Index Per Article: 20.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/24/2021] [Revised: 04/14/2021] [Accepted: 05/16/2021] [Indexed: 12/15/2022] Open
Abstract
Population-based studies that estimate awareness of nonalcoholic fatty liver disease (NAFLD) in the United States are scant. We aimed to understand public awareness of NAFLD and its temporal trends. Our study included 11,700 adults (18+ years old) from five National Health and Nutrition Examination Surveys (2007-2016). NAFLD was determined by the improved Fatty Liver Index for the multiethnic U.S. population (US-FLI) in the absence of secondary causes of liver disease. Overall prevalence of NAFLD, hepatitis C virus, and hepatitis B virus were 36.6%, 1.02% and 0.35%, respectively. From 2007-2008 to 2015-2016, awareness of liver disease among adults with NAFLD improved from 4.4% to 6.3% (trend P = 0.026) but 4 to 10 times lower than awareness about viral hepatitis. In 2015-2016, among adults with NAFLD, awareness of liver disease was lower among young adults (aged 18-29 years) compared with those aged ≥ 30 years (0% vs. 6.9%) and lower among non-Hispanic Blacks compared with other races (0.7% vs. 6.6%) (all P < 0.001). In multivariable analysis, young adults (adjusted odds ratio [aOR] = 0.29; confidence interval [CI] 0.10-0.87) and non-Hispanic Blacks (aOR = 0.43; CI 0.20-0.96) were negatively associated with awareness of liver disease among adults with NAFLD, whereas diabetes (aOR = 2.22; CI 1.37-3.58), advanced fibrosis (aOR = 2.34; CI 1.17-4.68), and a higher number of health care visits (aOR = 1.33; CI 1.15-1.50) were positively associated with awareness of liver disease. Nearly 96% of adults with NAFLD in the United States were unaware they had liver disease, especially among young adults and non-Hispanic Blacks. Findings indicate efforts are needed to improve awareness of NAFLD.
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Affiliation(s)
- Saleh A. Alqahtani
- Center for Outcomes Research in Liver DiseaseWashingtonDCUSA
- Division of Gastroenterology & HepatologyJohns Hopkins UniversityBaltimoreMDUSA
- Liver Transplant CenterKing Faisal Specialist Hospital & Research CenterRiyadhSaudi Arabia
| | - James M. Paik
- Center for Liver DiseaseDepartment of MedicineInova Fairfax Medical CampusFalls ChurchVAUSA
- Beatty Liver and Obesity Research ProgramInova Health SystemFalls ChurchVAUSA
| | - Rakesh Biswas
- Center for Liver DiseaseDepartment of MedicineInova Fairfax Medical CampusFalls ChurchVAUSA
| | - Tamoore Arshad
- Center for Liver DiseaseDepartment of MedicineInova Fairfax Medical CampusFalls ChurchVAUSA
| | - Linda Henry
- Center for Outcomes Research in Liver DiseaseWashingtonDCUSA
| | - Zobair M. Younossi
- Center for Liver DiseaseDepartment of MedicineInova Fairfax Medical CampusFalls ChurchVAUSA
- Beatty Liver and Obesity Research ProgramInova Health SystemFalls ChurchVAUSA
- Inova MedicineInova Health SystemFalls ChurchVAUSA
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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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Juanola O, Martínez-López S, Francés R, Gómez-Hurtado I. Non-Alcoholic Fatty Liver Disease: Metabolic, Genetic, Epigenetic and Environmental Risk Factors. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2021; 18:ijerph18105227. [PMID: 34069012 PMCID: PMC8155932 DOI: 10.3390/ijerph18105227] [Citation(s) in RCA: 166] [Impact Index Per Article: 41.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/23/2021] [Revised: 04/29/2021] [Accepted: 05/09/2021] [Indexed: 12/12/2022]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is one of the most frequent causes of chronic liver disease in the Western world, probably due to the growing prevalence of obesity, metabolic diseases, and exposure to some environmental agents. In certain patients, simple hepatic steatosis can progress to non-alcoholic steatohepatitis (NASH), which can sometimes lead to liver cirrhosis and its complications including hepatocellular carcinoma. Understanding the mechanisms that cause the progression of NAFLD to NASH is crucial to be able to control the advancement of the disease. The main hypothesis considers that it is due to multiple factors that act together on genetically predisposed subjects to suffer from NAFLD including insulin resistance, nutritional factors, gut microbiota, and genetic and epigenetic factors. In this article, we will discuss the epidemiology of NAFLD, and we overview several topics that influence the development of the disease from simple steatosis to liver cirrhosis and its possible complications.
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Affiliation(s)
- Oriol Juanola
- Gastroenterology and Hepatology, Translational Research Laboratory, Ente Ospedaliero Cantonale, Università della Svizzera Italiana, 6900 Lugano, Switzerland
| | - Sebastián Martínez-López
- Clinical Medicine Department, Miguel Hernández University, 03550 San Juan de Alicante, Spain
- Alicante Institute for Health and Biomedical Research (ISABIAL), Hospital General Universitario de Alicante, 03010 Alicante, Spain
| | - Rubén Francés
- Clinical Medicine Department, Miguel Hernández University, 03550 San Juan de Alicante, Spain
- Alicante Institute for Health and Biomedical Research (ISABIAL), Hospital General Universitario de Alicante, 03010 Alicante, Spain
- Networked Biomedical Research Center for Hepatic and Digestive Diseases (CIBERehd), Institute of Health Carlos III, 28029 Madrid, Spain
| | - Isabel Gómez-Hurtado
- Alicante Institute for Health and Biomedical Research (ISABIAL), Hospital General Universitario de Alicante, 03010 Alicante, Spain
- Networked Biomedical Research Center for Hepatic and Digestive Diseases (CIBERehd), Institute of Health Carlos III, 28029 Madrid, Spain
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Liu WY, Eslam M, Zheng KI, Ma HL, Rios RS, Lv MZ, Li G, Tang LJ, Zhu PW, Wang XD, Byrne CD, Targher G, George J, Zheng MH. Associations of Hydroxysteroid 17-beta Dehydrogenase 13 Variants with Liver Histology in Chinese Patients with Metabolic-associated Fatty Liver Disease. J Clin Transl Hepatol 2021; 9:194-202. [PMID: 34007801 PMCID: PMC8111109 DOI: 10.14218/jcth.2020.00151] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/05/2020] [Revised: 01/24/2021] [Accepted: 02/07/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND AND AIMS In Europeans, variants in the hydroxysteroid 17-beta dehydrogenase 13 (HSD17B13) gene impact liver histology in metabolic-associated fatty liver disease (MAFLD). The impact of these variants in ethnic Chinese is unknown. The aim of this study was to investigate the potential associations in Chinese patients. METHODS In total, 427 Han Chinese with biopsy-confirmed MAFLD were enrolled. Two single nucleotide polymorphisms in HSD17B13 were genotyped: rs72613567 and rs6531975. Logistic regression was used to test the association between the single nucleotide polymorphisms and liver histology. RESULTS In our cohort, the minor allele TA of the rs72613567 variant was related to an increased risk of fibrosis [odds ratio (OR): 2.93 (1.20-7.17), p=0.019 for the additive model; OR: 3.32 (1.39-7.91), p=0.007 for the recessive model], representing an inverse association as compared to the results from European cohorts. In contrast, we observed a protective effect on fibrosis for the minor A allele carriers of the HSD17B13 rs6531975 variant [OR: 0.48 (0.24-0.98), p=0.043 for the additive model; OR: 0.62 (0.40-0.94), p=0.025 for the dominant model]. HSD17B13 variants were only associated with fibrosis but no other histological features. Furthermore, HSD17B13 rs6531975 modulated the effect of PNPLA3 rs738409 on hepatic steatosis. CONCLUSIONS HSD17B13 rs72613567 is a risk variant for fibrosis in a Han Chinese MAFLD population but with a different direction for allelic association to that seen in Europeans. These data exemplify the need for studying diverse populations in genetic studies in order to fine map genome-wide association studies signals.
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Affiliation(s)
- Wen-Yue Liu
- Department of Endocrinology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Mohammed Eslam
- Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital and University of Sydney, Westmead, Sydney, Australia
| | - Kenneth I. Zheng
- NAFLD Research Center, Department of Hepatology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Hong-Lei Ma
- NAFLD Research Center, Department of Hepatology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Rafael S. Rios
- NAFLD Research Center, Department of Hepatology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Min-Zhi Lv
- Department of Biostatistics, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Gang Li
- NAFLD Research Center, Department of Hepatology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Liang-Jie Tang
- NAFLD Research Center, Department of Hepatology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Pei-Wu Zhu
- Department of Laboratory Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Xiao-Dong Wang
- NAFLD Research Center, Department of Hepatology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
- Institute of Hepatology, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Christopher D. Byrne
- Southampton National Institute for Health Research Biomedical Research Centre, University Hospital Southampton, Southampton General Hospital, Southampton, UK
| | - Giovanni Targher
- Section of Endocrinology, Diabetes and Metabolism, Department of Medicine, University and Azienda Ospedaliera Universitaria Integrata of Verona, Verona, Italy
| | - Jacob George
- Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital and University of Sydney, Westmead, Sydney, Australia
| | - Ming-Hua Zheng
- NAFLD Research Center, Department of Hepatology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
- Institute of Hepatology, Wenzhou Medical University, Wenzhou, Zhejiang, China
- Key Laboratory of Diagnosis and Treatment for The Development of Chronic Liver Disease in Zhejiang Province, Wenzhou, Zhejiang, China
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Lee GH, Phyo WW, Loo WM, Kwok R, Ahmed T, Shabbir A, So J, Koh CJ, Hartono JL, Muthiah M, Lim K, Tan PS, Lee YM, Lim SG, Dan YY. Validation of genetic variants associated with metabolic dysfunction-associated fatty liver disease in an ethnic Chinese population. World J Hepatol 2020; 12:1228-1238. [PMID: 33442450 PMCID: PMC7772735 DOI: 10.4254/wjh.v12.i12.1228] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/07/2020] [Revised: 09/28/2020] [Accepted: 10/15/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Genetic factors play an important role in the pathogenesis and development of metabolic dysfunction-associated fatty liver disease (MAFLD). AIM To study the association of single nucleotide polymorphisms (SNPs), previously identified in Western populations, with the risk of MAFLD in a Singapore Chinese population and their interactions with environmental and medical risk factors. METHODS A retrospective case-control study was conducted with 72 MAFLD cases and 72 controls with no hepatic steatosis on computed tomography, magnetic resonance imaging, or controlled attenuation parameter score. Subjects were recruited from two tertiary hospitals. Genetic alleles such as NCAN, GCKR, LYPLAL1, PNPLA3, PPP1R3B, FDFT1, COL13A1, EFCAB4B, PZP, and TM6SF2 were genotyped using the TaqMan® Predesigned SNP Genotyping Assay. RESULTS Weight and body mass index (BMI) were 1.2-times higher in patients (70.6 kg, 95% confidence interval [CI]: 57.1-84.1 vs 60.8 kg, 95%CI: 48.5-73.1, P < 0.001 and 26.9 kg, 95%CI: 23-40.8 vs 23.3 kg 95%CI: 19-27.6, P < 0.001 respectively). The prevalence of diabetes mellitus in patients was 40.3% and 20.8% in controls (P = 0.011). Patients had higher mean triglycerides than controls (P < 0.001). PNPLA3 GG was more likely to be associated with MAFLD (43.4% CC vs 69.7% GG, P = 0.017, and 44.8% CG vs 69.7% GG, P = 0.022). In multivariable analysis, hypertriglyceridemia (odds ratio [OR]: 2.04 95%CI: 1.3-3.1, P = 0.001), BMI (OR: 1.2 95%CI: 1.1-1.4, P < 0.001) and PNPLA3 GG (OR: 3.4 95%CI: 1.3-9.2, P = 0.014) were associated with MAFLD (area under the receiver operating characteristic curve of 0.823). CONCLUSION Among the Chinese population of Singapore, PNPLA3 homozygous GG allele is a strong predictor of MAFLD, whereas LYPLAL1, GCKR, FDFT1, COL13A1, PZP, and TM6SF2 are not significantly associated. Hypertriglyceridemia, high BMI, and PNPLA3 GG are independent predictors of MAFLD.
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Affiliation(s)
- Guan Huei Lee
- Division of Gastroenterology and Hepatology, Department of Medicine, National University Health System, Singapore 119228, Singapore
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Singapore.
| | - Wah Wah Phyo
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Singapore
| | - Wai Mun Loo
- Division of Gastroenterology and Hepatology, Department of Medicine, National University Health System, Singapore 119228, Singapore
| | - Raymond Kwok
- Department of Medicine, Khoo Teck Puat Hospital, Singapore 768828, Singapore
| | - Taufique Ahmed
- Department of Medicine, Khoo Teck Puat Hospital, Singapore 768828, Singapore
| | - Asim Shabbir
- Department of Surgery, National University Health System, Singapore 119228, Singapore
| | - Jimmy So
- Department of Surgery, National University Health System, Singapore 119228, Singapore
| | - Calvin Jianyi Koh
- Division of Gastroenterology and Hepatology, Department of Medicine, National University Health System, Singapore 119228, Singapore
| | - Juanda Leo Hartono
- Division of Gastroenterology and Hepatology, Department of Medicine, National University Health System, Singapore 119228, Singapore
| | - Mark Muthiah
- Division of Gastroenterology and Hepatology, Department of Medicine, National University Health System, Singapore 119228, Singapore
| | - Kieron Lim
- Division of Gastroenterology and Hepatology, Department of Medicine, National University Health System, Singapore 119228, Singapore
| | - Poh Seng Tan
- Division of Gastroenterology and Hepatology, Department of Medicine, National University Health System, Singapore 119228, Singapore
| | - Yin Mei Lee
- Division of Gastroenterology and Hepatology, Department of Medicine, National University Health System, Singapore 119228, Singapore
| | - Seng Gee Lim
- Division of Gastroenterology and Hepatology, Department of Medicine, National University Health System, Singapore 119228, Singapore
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Singapore
| | - Yock Young Dan
- Division of Gastroenterology and Hepatology, Department of Medicine, National University Health System, Singapore 119228, Singapore
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Singapore
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Rives C, Fougerat A, Ellero-Simatos S, Loiseau N, Guillou H, Gamet-Payrastre L, Wahli W. Oxidative Stress in NAFLD: Role of Nutrients and Food Contaminants. Biomolecules 2020; 10:E1702. [PMID: 33371482 PMCID: PMC7767499 DOI: 10.3390/biom10121702] [Citation(s) in RCA: 92] [Impact Index Per Article: 18.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2020] [Revised: 12/14/2020] [Accepted: 12/15/2020] [Indexed: 12/14/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is often the hepatic expression of metabolic syndrome and its comorbidities that comprise, among others, obesity and insulin-resistance. NAFLD involves a large spectrum of clinical conditions. These range from steatosis, a benign liver disorder characterized by the accumulation of fat in hepatocytes, to non-alcoholic steatohepatitis (NASH), which is characterized by inflammation, hepatocyte damage, and liver fibrosis. NASH can further progress to cirrhosis and hepatocellular carcinoma. The etiology of NAFLD involves both genetic and environmental factors, including an unhealthy lifestyle. Of note, unhealthy eating is clearly associated with NAFLD development and progression to NASH. Both macronutrients (sugars, lipids, proteins) and micronutrients (vitamins, phytoingredients, antioxidants) affect NAFLD pathogenesis. Furthermore, some evidence indicates disruption of metabolic homeostasis by food contaminants, some of which are risk factor candidates in NAFLD. At the molecular level, several models have been proposed for the pathogenesis of NAFLD. Most importantly, oxidative stress and mitochondrial damage have been reported to be causative in NAFLD initiation and progression. The aim of this review is to provide an overview of the contribution of nutrients and food contaminants, especially pesticides, to oxidative stress and how they may influence NAFLD pathogenesis.
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Affiliation(s)
- Clémence Rives
- Toxalim (Research Center in Food Toxicology), Université de Toulouse, INRA, EVT, INP-Purpan, UPS, 31300 Toulouse, France; (C.R.); (A.F.); (S.E.-S.); (N.L.); (H.G.)
| | - Anne Fougerat
- Toxalim (Research Center in Food Toxicology), Université de Toulouse, INRA, EVT, INP-Purpan, UPS, 31300 Toulouse, France; (C.R.); (A.F.); (S.E.-S.); (N.L.); (H.G.)
| | - Sandrine Ellero-Simatos
- Toxalim (Research Center in Food Toxicology), Université de Toulouse, INRA, EVT, INP-Purpan, UPS, 31300 Toulouse, France; (C.R.); (A.F.); (S.E.-S.); (N.L.); (H.G.)
| | - Nicolas Loiseau
- Toxalim (Research Center in Food Toxicology), Université de Toulouse, INRA, EVT, INP-Purpan, UPS, 31300 Toulouse, France; (C.R.); (A.F.); (S.E.-S.); (N.L.); (H.G.)
| | - Hervé Guillou
- Toxalim (Research Center in Food Toxicology), Université de Toulouse, INRA, EVT, INP-Purpan, UPS, 31300 Toulouse, France; (C.R.); (A.F.); (S.E.-S.); (N.L.); (H.G.)
| | - Laurence Gamet-Payrastre
- Toxalim (Research Center in Food Toxicology), Université de Toulouse, INRA, EVT, INP-Purpan, UPS, 31300 Toulouse, France; (C.R.); (A.F.); (S.E.-S.); (N.L.); (H.G.)
| | - Walter Wahli
- Toxalim (Research Center in Food Toxicology), Université de Toulouse, INRA, EVT, INP-Purpan, UPS, 31300 Toulouse, France; (C.R.); (A.F.); (S.E.-S.); (N.L.); (H.G.)
- Lee Kong Chian School of Medicine, Nanyang Technological University Singapore, Clinical Sciences Building, 11 Mandalay Road, Singapore 308232, Singapore
- Center for Integrative Genomics, Université de Lausanne, Le Génopode, CH-1015 Lausanne, Switzerland
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Al-Qarni R, Iqbal M, Al-Otaibi M, Al-Saif F, Alfadda AA, Alkhalidi H, Bamehriz F, Hassanain M. Validating candidate biomarkers for different stages of non-alcoholic fatty liver disease. Medicine (Baltimore) 2020; 99:e21463. [PMID: 32898995 PMCID: PMC7478685 DOI: 10.1097/md.0000000000021463] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a common chronic condition caused by the accumulation of fat in the liver. NAFLD may range from simple steatosis to advanced cirrhosis, and affects more than 1 billion people around the world. To date, there has been no effective treatment for NAFLD. In this study, we evaluated the expression of 4 candidate NAFLD biomarkers to assess their possible applicability in the classification and treatment of the disease.Twenty-six obese subjects, who underwent bariatric surgery, were recruited and their liver biopsies obtained. Expression of 4 candidate biomarker genes, PNPLA3, COL1A1, PPP1R3B, and KLF6 were evaluated at gene and protein levels by RT-qPCR and enzyme-linked immunosorbent assay (ELISA), respectively.A significant increase in the levels of COL1A1 protein (P = .03) and PNPLA3 protein (P = .03) were observed in patients with fibrosis-stage NAFLD compared to that in patients with steatosis-stage NAFLD. However, no significant differences were found in abundance of PPP1R3B and KLF6 proteins or at the gene level for any of the candidate.This is the first study, to our knowledge, to report on the expression levels of candidate biomarker genes for NAFLD in the Saudi population. Although PNPLA3 and PPP1R3B had been previously suggested as biomarkers for steatosis and KLF6 as a possible marker for the fibrosis stage of NAFLD, our results did not support these findings. However, other studies that had linked PNPLA3 to fibrosis in advanced NAFLD supported our current finding of high PNPLA3 protein in patients with fibrosis. Additionally, our results support COL1A1 protein as a potential biomarker for the fibrosis stage of NAFLD, and indicate its use in the screening of patients with NAFLD. Further studies are required to validate the use of COL1A1 as a biomarker for advanced NAFLD in a larger cohort.
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Affiliation(s)
| | | | | | - Faisal Al-Saif
- Department of Surgery, College of Medicine, King Saud University, Riyadh, Saudi Arabia
| | | | | | - Fahad Bamehriz
- Department of Surgery, College of Medicine, King Saud University, Riyadh, Saudi Arabia
| | - Mazen Hassanain
- Department of Surgery, College of Medicine, King Saud University, Riyadh, Saudi Arabia
- Department of Oncology, McGill University, Montreal, Quebec, Canada
- Liver Disease Research Center, King Saud University, Riyadh, Saudi Arabia
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Saiman Y, Hooks R, Carr RM. High-Risk Groups for Non-alcoholic Fatty Liver and Non-alcoholic Steatohepatitis Development and Progression. ACTA ACUST UNITED AC 2020. [DOI: 10.1007/s11901-020-00539-5] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
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Patel P, Muller C, Paul S. Racial disparities in nonalcoholic fatty liver disease clinical trial enrollment: A systematic review and meta-analysis. World J Hepatol 2020; 12:506-518. [PMID: 32952877 PMCID: PMC7475777 DOI: 10.4254/wjh.v12.i8.506] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/13/2020] [Revised: 07/09/2020] [Accepted: 07/26/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Non-alcoholic fatty liver disease (NAFLD) has a heterogeneous distribution across racial and ethnic groups, with a disproportionate burden among Hispanics. Although there are currently no approved therapies for treatment of NAFLD, several therapies have been investigated in clinical trials.
AIM To analyze the inclusion of racial and ethnic minority groups in clinical trials for NAFLD.
METHODS We performed a systematic review of North American, English-language, prospective studies for NAFLD therapies published from 2005 to 2019. Racial and ethnic enrollment data were recorded for each eligible study. Meta-analysis was performed to compute pooled prevalence of different racial and ethnic groups, followed by further subgroup analyses. These analyses were based on diagnosis of non-alcoholic steatohepatitis (NASH) and timing of study on enrollment by ethnicity. Descriptive statistics were performed to compare racial and ethnic study enrollment to previously reported NAFLD population prevalence.
RESULTS Thirty-eight studies met criteria for inclusion in the systematic review. When reported, median age of enrolled subjects was 49 years (range 41.5-58) with 56% female participants. NAFLD was defined through biopsy findings in 79% (n = 30) of the studies. Of the included articles, treatment modalities ranged from medications (n = 28, 74%), lifestyle interventions (n = 5, 13%), bariatric surgery (n = 4, 11%) and phlebotomy (n = 1, 2%). Twenty-eight studies (73%) included racial and/or ethnic demographic information, while only 17 (45%) included information regarding Hispanic participation. Of the 2983 patients enrolled in all eligible trials, a total of only 346 (11.6%) Hispanic participants was reported. Meta-analysis revealed a pooled Hispanic prevalence of 24.3% (95% confidence interval 16.6-32.0, I2 94.6%) among studies documenting Hispanic enrollment. Hispanic enrollment increased over time from 15% from 2005-2014 to 37% from 2015-2019.
CONCLUSION In a meta-analysis of NAFLD trials, documentation of racial/ethnic demographic data occurred in less than half of studies. Standardization of reporting of race/ethnicity and targeted interventions toward minority recruitment are needed to improve diversity of enrollment.
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Affiliation(s)
- Parita Patel
- Section of Gastroenterology, Hepatology, and Nutrition, University of Chicago Medical Center, Chicago, IL 60637, United States
| | - Charles Muller
- Section of Gastroenterology, Hepatology, and Nutrition, University of Chicago Medical Center, Chicago, IL 60637, United States
| | - Sonali Paul
- Section of Gastroenterology, Hepatology, and Nutrition, University of Chicago Medical Center, Chicago, IL 60637, United States
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Gender-specific differences in clinical and metabolic variables associated with NAFLD in a Mexican pediatric population. Ann Hepatol 2020; 18:693-700. [PMID: 31151875 DOI: 10.1016/j.aohep.2019.04.012] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2018] [Revised: 04/05/2019] [Accepted: 02/08/2019] [Indexed: 02/04/2023]
Abstract
INTRODUCTION AND OBJECTIVES Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease in children and it is more prevalent in Hispanic males. The gender differences can be explained by body fat distribution, lifestyle, or sex hormone metabolism. We evaluated anthropometric and metabolic differences by gender in children with and without NAFLD. METHODS We included 194 participants (eutrophic, overweight, and individuals with obesity). The presence of NAFLD was determined using ultrasonography, and we evaluated the association between this disease with metabolic and anthropometric variables by gender. RESULTS The mean age was 10.64±2.54 years. The frequency of NAFLD in boys was 24.51% and in girls was 11.96% (OR=2.39; 95%CI=1.10-5.19; p=0.025). For girls, NAFLD was significantly associated with triglycerides (p=0.012), homeostatic model assessment of insulin resistance (HOMA-IR) (p=0.048), and the visceral adiposity index (VAI) (p=0.024). The variables related to NAFLD in a gender-specific manner were body mass index (BMI) (p=0.001), waist circumference (WC) (p<0.001), HDL cholesterol (p=0.021), alanine aminotransferase (ALT) (p<0.001), and aspartate aminotransferase (AST) (p=0.002). CONCLUSIONS In our study NAFLD is more frequent in boys, only ALT, and no other clinical or metabolic variables, were associated with NAFLD in these patients. HOMA-IR, VAI, triglyceride levels, and ALT were associated with NAFLD only in girls. The ALT cut-off points for the development of NAFLD in our study were 28.5U/L in females and 27.5U/L in males. Our findings showed that NAFLD should be intentionally screened in patients with obesity, particularly in boys.
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Fatty liver diseases, mechanisms, and potential therapeutic plant medicines. Chin J Nat Med 2020; 18:161-168. [PMID: 32245585 DOI: 10.1016/s1875-5364(20)30017-0] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2019] [Indexed: 02/07/2023]
Abstract
The liver is an important metabolic organ and controls lipid, glucose and energy metabolism. Dysruption of hepatic lipid metabolism is often associated with fatty liver diseases, including nonalcoholic fatty liver disease (NAFLD), alcoholic fatty liver diseases (AFLD) and hyperlipidemia. Recent studies have uncovered the contribution of hormones, transcription factors, and inflammatory cytokines to the pathogenesis of dyslipidemia and fatty liver diseases. Moreover, a significant amount of effort has been put to examine the mechanisms underlying the potential therapeutic effects of many natural plant products on fatty liver diseases and metabolic diseases. We review the current understanding of insulin, thyroid hormone and inflammatory cytokines in regulating hepatic lipid metabolism, focusing on several essential transcription regulators, such as Sirtuins (SIRTs), Forkhead box O (FoxO), Sterol-regulatory element-binding proteins (SREBPs). We also discuss a few representative natural products with promising thereapeutic effects on fatty liver disease and dyslipidemia.
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Unalp-Arida A, Ruhl CE. Patatin-Like Phospholipase Domain-Containing Protein 3 I148M and Liver Fat and Fibrosis Scores Predict Liver Disease Mortality in the U.S. Population. Hepatology 2020; 71:820-834. [PMID: 31705824 DOI: 10.1002/hep.31032] [Citation(s) in RCA: 58] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/17/2019] [Accepted: 11/03/2019] [Indexed: 12/11/2022]
Abstract
BACKGROUND AND AIMS Fatty liver causes premature death worldwide and requires long-term health care. We examined relationships of liver disease markers, including patatin-like phospholipase domain-containing protein 3 (PNPLA3) I148M, with mortality in the U.S. National Health and Nutrition Examination Survey, 1988-1994, with 27 years of linked mortality data. APPROACH AND RESULTS We studied 13,298 viral hepatitis negative adults who fasted at least 4 hours using the nonalcoholic fatty liver disease (NAFLD) liver fat score and NAFLD fibrosis score. PNPLA3 I148M was genotyped in a subgroup of participants from 1991 to 1994 (n = 5,640). Participants were passively followed for mortality, identified by death certificate underlying or contributing causes, by linkage to the National Death Index through 2015. During follow-up (median, 23.2 years), cumulative mortality was 33.2% overall and 1.1% with liver disease, including primary liver cancer. Increased liver disease mortality was associated with PNPLA3 I148M (hazard ratio [HR], 2.9; 95% confidence interval [CI], 0.9-9.8) and 148M genotypes (HR, 18.2; 95% CI, 3.5-93.8), an intermediate (HR, 3.8; 95% CI, 1.3-10.7) or high (HR, 12.6; 95% CI, 4.3-36.3) NAFLD liver fat score, and a high NAFLD fibrosis score (HR, 12.2; 95% CI, 1.9-80.6) adjusted for risk factors. Survival curves suggest that increased mortality risk with two 148M alleles was greatest beginning in the second decade of follow-up. Overall, but not cardiovascular disease, mortality was associated with the PNPLA3 148M allele, and both mortality outcomes were associated with higher fat and fibrosis scores. CONCLUSIONS In the U.S. population, PNPLA3 I148M and higher NAFLD liver fat and fibrosis scores were associated with increased liver disease mortality. Genetic variant PNPLA3 I148M may complement other liver disease markers for NAFLD surveillance.
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Affiliation(s)
- Aynur Unalp-Arida
- Department of Health and Human Services, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD
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