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Ben Salem A, Ezzidi I, Ben Abdennebi H, Mtiraoui N, Sarray S. A novel link between KCNQ1 genetic variants and polycystic ovary syndrome susceptibility. Biomed Rep 2025; 22:104. [PMID: 40322554 PMCID: PMC12046284 DOI: 10.3892/br.2025.1982] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2024] [Accepted: 04/02/2025] [Indexed: 05/08/2025] Open
Abstract
Genome-wide association studies (GWAS) have identified the potassium voltage-gated channel subfamily Q member 1 (KCNQ1) gene, as a potential contributor to the pathogenesis of type 2 diabetes (T2D). Given the known genetic overlap between T2D and polycystic ovary syndrome (PCOS), the present study aimed to investigate the potential association between KCNQ1 gene variants and PCOS susceptibility in a population of Tunisian women. A total of 230 patients and 230 healthy controls were recruited for this case control study. The Rotterdam consensus criteria were used to diagnose patients with PCOS. Genotyping of three KCNQ1 variants (rs231361, rs151290 and rs2237895), was performed using allelic discrimination (real-time PCR). After excluding false positive associations using the false discovery rate adjustment and ensuring statistical power >80%, the present results suggested that the KCNQ1 gene may play a role in PCOS susceptibility. Specifically, the rs231361 variant showed a significant association with an increased risk of PCOS through multiple genetic inheritance models. Additionally, the A/A genotype of the rs231361 variant displayed a correlation with increased levels of triglycerides compared with those with the G/G wild-type and the G/A heterozygous genotypes. To the best of our knowledge, this is the first study to identify the KCNQ1 rs231361 variant as a potential genetic risk factor for PCOS. These findings have important implications for risk assessment and the development of personalized treatment approaches for affected women.
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Affiliation(s)
- Assila Ben Salem
- Laboratory of Human Genome and Multifactorial Diseases (LR12ES07), Faculty of Pharmacy of Monastir, University of Monastir, 5000 Monastir, Tunisia
| | - Intissar Ezzidi
- Laboratory of Human Genome and Multifactorial Diseases (LR12ES07), Faculty of Pharmacy of Monastir, University of Monastir, 5000 Monastir, Tunisia
- Higher Institute of Biotechnology of Monastir, University of Monastir, 5000 Monastir, Tunisia
| | - Hassen Ben Abdennebi
- Laboratory of Human Genome and Multifactorial Diseases (LR12ES07), Faculty of Pharmacy of Monastir, University of Monastir, 5000 Monastir, Tunisia
| | - Nabil Mtiraoui
- Laboratory of Human Genome and Multifactorial Diseases (LR12ES07), Faculty of Pharmacy of Monastir, University of Monastir, 5000 Monastir, Tunisia
- Higher Institute of Biotechnology of Monastir, University of Monastir, 5000 Monastir, Tunisia
| | - Sameh Sarray
- College of Medicine and Health Sciences, Arabian Gulf University, 0329 Manama, Kingdom of Bahrain
- Faculty of Sciences, University of Tunis EL Manar, 2092 Tunis, Tunisia
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2
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Lee H, Fernandes M, Lee J, Merino J, Kwak SH. Exploring the shared genetic landscape of diabetes and cardiovascular disease: findings and future implications. Diabetologia 2025; 68:1087-1100. [PMID: 40088285 PMCID: PMC12069157 DOI: 10.1007/s00125-025-06403-9] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/21/2024] [Accepted: 01/28/2025] [Indexed: 03/17/2025]
Abstract
Diabetes is a rapidly growing global health concern projected to affect one in eight adults by 2045, which translates to roughly 783 million people. The profound metabolic alterations often present in dysglycaemia significantly increase the risk of cardiovascular complications. While genetic susceptibility plays a crucial role in diabetes and its vascular complications, identifying genes and molecular mechanisms that influence both diseases simultaneously has proven challenging. A key reason for this challenge is the pathophysiological heterogeneity underlying these diseases, with multiple processes contributing to different forms of diabetes and specific cardiovascular complications. This molecular heterogeneity has limited the effectiveness of large-scale genome-wide association studies (GWAS) in identifying shared underlying mechanisms. Additionally, our limited knowledge of the causal genes, cell types and disease-relevant states through which GWAS signals operate has hindered the discovery of common molecular pathways. This review highlights recent advances in genetic epidemiology, including studies of causal associations that have uncovered genetic and molecular factors influencing both dysglycaemia and cardiovascular complications. We explore how disease subtyping approaches can be critical in pinpointing the unique molecular signatures underlying both diabetes and cardiovascular complications. Finally, we address critical research gaps and future opportunities to advance our understanding of both diseases and translate these discoveries into tangible benefits for patient care and population health.
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Affiliation(s)
- Hyunsuk Lee
- Department of Internal Medicine, Seoul National University College of Medicine and Seoul National University Hospital, Seoul, Korea
- Department of Translational Medicine, Seoul National University College of Medicine, Seoul, Korea
- Genomic Medicine Institute, Medical Research Center, Seoul National University College of Medicine, Seoul, Korea
| | - Maria Fernandes
- Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark
| | - Jeongeun Lee
- Department of Internal Medicine, Seoul National University College of Medicine and Seoul National University Hospital, Seoul, Korea
| | - Jordi Merino
- Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark.
- Diabetes Unit, Endocrine Division, Massachusetts General Hospital, Boston, MA, USA.
- Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
| | - Soo Heon Kwak
- Department of Internal Medicine, Seoul National University College of Medicine and Seoul National University Hospital, Seoul, Korea.
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3
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Knowles EEM, Peralta JM, Rodrigue AL, Mathias SR, Mollon J, Leandro AC, Curran JE, Blangero J, Glahn DC. Differential gene expression study in whole blood identifies candidate genes for psychosis in African American individuals. Schizophr Res 2025; 280:85-94. [PMID: 40267851 DOI: 10.1016/j.schres.2025.04.018] [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: 06/26/2023] [Revised: 03/10/2025] [Accepted: 04/13/2025] [Indexed: 04/25/2025]
Abstract
Genome-wide association has identified regions of the genome that mediate risk for psychosis. It is possible that variants in these regions confer risk by altering gene expression. This work has predominantly been conducted in individuals of European descent and has focused narrowly on schizophrenia rather than psychosis as a syndrome. In the present study we investigated alterations in gene expression in African American individuals with a range of psychotic diagnoses to increase understanding of the etiology in an underserved population. We performed RNA-seq in whole bloody to survey the transcriptome in 126 patients with a psychosis-spectrum disorder and 217 healthy controls and applied differential gene expression analyses across the genome while controlling for age, sex, population stratification and batch. We found 18 differentially expressed genes (DEGs), some of the locations of the corresponding genes overlap with previously implicated regions for psychosis, but many of which were novel associations. Enrichment analysis of nominally significant genes (p < 0.05) revealed overrepresentation of biological processes relating to platelet, immune and cellular function, and sensory perception. Weighted gene co-expression network analysis, applied to identify modules of co-expressed genes associated with psychosis, revealed 10 modules, one of which was significantly associated with psychosis. This module was significantly enriched for DEGs, and for platelet function. These results support the potential role of immune function in the etiology of psychosis, identify novel candidate gene expression phenotypes that correspond to both established and new genomic regions, in individuals of African American ancestry.
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Affiliation(s)
- E E M Knowles
- Department of Psychiatry, Boston Children's Hospital, Boston, MA, USA; Department of Psychiatry, Harvard Medical School, Boston, MA, USA.
| | - J M Peralta
- South Texas Diabetes and Obesity Institute and Department of Human Genetics, University of Texas Rio Grande Valley School of Medicine, Brownsville, TX, USA
| | - A L Rodrigue
- Department of Psychiatry, Boston Children's Hospital, Boston, MA, USA; Department of Psychiatry, Harvard Medical School, Boston, MA, USA
| | - S R Mathias
- Department of Psychiatry, Boston Children's Hospital, Boston, MA, USA; Department of Psychiatry, Harvard Medical School, Boston, MA, USA
| | - J Mollon
- Department of Psychiatry, Boston Children's Hospital, Boston, MA, USA; Department of Psychiatry, Harvard Medical School, Boston, MA, USA
| | - A C Leandro
- South Texas Diabetes and Obesity Institute and Department of Human Genetics, University of Texas Rio Grande Valley School of Medicine, Brownsville, TX, USA
| | - J E Curran
- South Texas Diabetes and Obesity Institute and Department of Human Genetics, University of Texas Rio Grande Valley School of Medicine, Brownsville, TX, USA
| | - J Blangero
- South Texas Diabetes and Obesity Institute and Department of Human Genetics, University of Texas Rio Grande Valley School of Medicine, Brownsville, TX, USA
| | - D C Glahn
- Department of Psychiatry, Boston Children's Hospital, Boston, MA, USA; Department of Psychiatry, Harvard Medical School, Boston, MA, USA; Olin Neuropsychiatric Research Center, Institute of Living, Hartford Hospital, Hartford, CT, USA
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Afrifa‐Yamoah E, Adua E, Peprah‐Yamoah E, Anto EO, Opoku‐Yamoah V, Acheampong E, Macartney MJ, Hashmi R. Pathways to chronic disease detection and prediction: Mapping the potential of machine learning to the pathophysiological processes while navigating ethical challenges. Chronic Dis Transl Med 2025; 11:1-21. [PMID: 40051825 PMCID: PMC11880127 DOI: 10.1002/cdt3.137] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2024] [Revised: 04/03/2024] [Accepted: 05/27/2024] [Indexed: 03/09/2025] Open
Abstract
Chronic diseases such as heart disease, cancer, and diabetes are leading drivers of mortality worldwide, underscoring the need for improved efforts around early detection and prediction. The pathophysiology and management of chronic diseases have benefitted from emerging fields in molecular biology like genomics, transcriptomics, proteomics, glycomics, and lipidomics. The complex biomarker and mechanistic data from these "omics" studies present analytical and interpretive challenges, especially for traditional statistical methods. Machine learning (ML) techniques offer considerable promise in unlocking new pathways for data-driven chronic disease risk assessment and prognosis. This review provides a comprehensive overview of state-of-the-art applications of ML algorithms for chronic disease detection and prediction across datasets, including medical imaging, genomics, wearables, and electronic health records. Specifically, we review and synthesize key studies leveraging major ML approaches ranging from traditional techniques such as logistic regression and random forests to modern deep learning neural network architectures. We consolidate existing literature to date around ML for chronic disease prediction to synthesize major trends and trajectories that may inform both future research and clinical translation efforts in this growing field. While highlighting the critical innovations and successes emerging in this space, we identify the key challenges and limitations that remain to be addressed. Finally, we discuss pathways forward toward scalable, equitable, and clinically implementable ML solutions for transforming chronic disease screening and prevention.
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Affiliation(s)
| | - Eric Adua
- Rural Clinical School, Medicine and HealthUniversity of New South WalesSydneyNew South WalesAustralia
- School of Medical and Health SciencesEdith Cowan UniversityJoondalupWestern AustraliaAustralia
| | | | - Enoch O. Anto
- School of Medical and Health SciencesEdith Cowan UniversityJoondalupWestern AustraliaAustralia
- Department of Medical Diagnostics, Faculty of Allied Health Sciences, College of Health SciencesKwame Nkrumah University of Science and TechnologyKumasiGhana
| | - Victor Opoku‐Yamoah
- School of Optometry and Vision ScienceUniversity of WaterlooWaterlooOntarioCanada
| | - Emmanuel Acheampong
- Department of Genetics and Genome BiologyLeicester Cancer Research CentreUniversity of LeicesterLeicesterUK
| | - Michael J. Macartney
- Faculty of Science Medicine and HealthUniversity of WollongongWollongongNew South WalesAustralia
| | - Rashid Hashmi
- Rural Clinical School, Medicine and HealthUniversity of New South WalesSydneyNew South WalesAustralia
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Bonnefond A, Florez JC, Loos RJF, Froguel P. Dissection of type 2 diabetes: a genetic perspective. Lancet Diabetes Endocrinol 2025; 13:149-164. [PMID: 39818223 DOI: 10.1016/s2213-8587(24)00339-5] [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: 07/14/2024] [Revised: 09/11/2024] [Accepted: 10/30/2024] [Indexed: 01/18/2025]
Abstract
Diabetes is a leading cause of global mortality and disability, and its economic burden is substantial. This Review focuses on type 2 diabetes, which makes up 90-95% of all diabetes cases. Type 2 diabetes involves a progressive loss of insulin secretion often alongside insulin resistance and metabolic syndrome. Although obesity and a sedentary lifestyle are considerable contributors, research over the last 25 years has shown that type 2 diabetes develops on a predisposing genetic background, with family and twin studies indicating considerable heritability (ie, 31-72%). This Review explores type 2 diabetes from a genetic perspective, highlighting insights into its pathophysiology and the implications for precision medicine. More specifically, the traditional understanding of type 2 diabetes genetics has focused on a dichotomy between monogenic and polygenic forms. However, emerging evidence suggests a continuum that includes monogenic, oligogenic, and polygenic contributions, revealing their complementary roles in type 2 diabetes pathophysiology. Recent genetic studies provide deeper insights into disease mechanisms and pave the way for precision medicine approaches that could transform type 2 diabetes management. Additionally, the effect of environmental factors on type 2 diabetes, particularly from epigenetic modifications, adds another layer of complexity to understanding and addressing this multifaceted disease.
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Affiliation(s)
- Amélie Bonnefond
- Université de Lille, Inserm UMR1283, CNRS UMR8199, European Genomic Institute for Diabetes (EGID), Institut Pasteur de Lille, Lille University Hospital, Lille, France; Department of Metabolism, Imperial College London, London, UK.
| | - Jose C Florez
- Center for Genomic Medicine and Diabetes Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA; Programs in Metabolism and Medical and Population Genetics, Broad Institute, Cambridge, MA, USA; Department of Medicine, Harvard Medical School, Boston, MA, USA
| | - Ruth J F Loos
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Philippe Froguel
- Université de Lille, Inserm UMR1283, CNRS UMR8199, European Genomic Institute for Diabetes (EGID), Institut Pasteur de Lille, Lille University Hospital, Lille, France; Department of Metabolism, Imperial College London, London, UK.
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Jia W, Chan JC, Wong TY, Fisher EB. Diabetes in China: epidemiology, pathophysiology and multi-omics. Nat Metab 2025; 7:16-34. [PMID: 39809974 DOI: 10.1038/s42255-024-01190-w] [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: 11/28/2023] [Accepted: 11/25/2024] [Indexed: 01/16/2025]
Abstract
Although diabetes is now a global epidemic, China has the highest number of affected people, presenting profound public health and socioeconomic challenges. In China, rapid ecological and lifestyle shifts have dramatically altered diabetes epidemiology and risk factors. In this Review, we summarize the epidemiological trends and the impact of traditional and emerging risk factors on Chinese diabetes prevalence. We also explore recent genetic, metagenomic and metabolomic studies of diabetes in Chinese, highlighting their role in pathogenesis and clinical management. Although heterogeneity across these multidimensional areas poses major analytic challenges in classifying patterns or features, they have also provided an opportunity to increase the accuracy and specificity of diagnosis for personalized treatment and prevention. National strategies and ongoing research are essential for improving diabetes detection, prevention and control, and for personalizing care to alleviate societal impacts and maintain quality of life.
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Affiliation(s)
- Weiping Jia
- Shanghai Key Laboratory of Diabetes Mellitus, Department of Endocrinology and Metabolism, Shanghai Diabetes Institute, Shanghai Clinical Center for Diabetes, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
- Institute for Proactive Healthcare, Shanghai Jiao Tong University, Shanghai, China.
| | - Juliana Cn Chan
- Department of Medicine and Therapeutics, Li Ka Shing Institute of Health Sciences and Hong Kong Institute of Diabetes and Obesity, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong, China
| | - Tien Y Wong
- Tsinghua Medicine, Beijing Tsinghua Changgung Hospital, Tsinghua University, Beijing, China
- Singapore National Eye Center, SingHealth, Singapore, Singapore
| | - Edwin B Fisher
- Peers for Progress, Department of Health Behavior, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
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Wu F, Hu X, Li X, Huang Y. Identification of KCNQ1 as a diagnostic biomarker related to endoplasmic reticulum stress for intervertebral disc degeneration based on machine learning and experimental evidence. Medicine (Baltimore) 2024; 103:e40661. [PMID: 39612444 PMCID: PMC11608675 DOI: 10.1097/md.0000000000040661] [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: 06/02/2024] [Accepted: 11/06/2024] [Indexed: 12/01/2024] Open
Abstract
Intervertebral disc degeneration (IDD) is a primary cause of low back pain and disability. Cellular senescence and apoptosis due to endoplasmic reticulum stress (ERS) are key in IDD pathology. Identifying biomarkers linked to ERS in IDD is crucial for diagnosis and treatment. We utilized machine learning on gene expression profiles from the Gene Expression Omnibus database to discover biomarkers associated with ERS in IDD. Gene set enrichment analysis (GSEA) and single-sample GSEA were applied to evaluate the immunological features and biological functions of these biomarkers. The expression of KCNQ1 was experimentally validated. Machine learning identified KCNQ1 as a diagnostic biomarker for ERS in IDD, confirmed by Western blotting. GSEA indicated that KCNQ1 influences IDD primarily through the Notch signaling pathway and by regulating macrophage and monocyte infiltration. KCNQ1, identified as an ERS-associated biomarker in IDD, impacts the Notch signaling pathway and immune cell infiltration, suggesting its potential as a therapeutic target for IDD. Further validation through prospective studies and additional experimental methods is necessary to elucidate the role of KCNQ1 in IDD comprehensively.
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Affiliation(s)
- Feng Wu
- Department of Orthopaedics, Pingxiang People’s Hospital, Pingxiang, Jiangxi, China
| | - Xin Hu
- Department of Orthopaedics, Pingxiang People’s Hospital, Pingxiang, Jiangxi, China
| | - Xing Li
- Department of Orthopaedics, Pingxiang People’s Hospital, Pingxiang, Jiangxi, China
| | - Yongquan Huang
- Department of Orthopaedics, Pingxiang People’s Hospital, Pingxiang, Jiangxi, China
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8
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Imamura M, Maeda S. Genetic studies of type 2 diabetes, and microvascular complications of diabetes. Diabetol Int 2024; 15:699-706. [PMID: 39469559 PMCID: PMC11512959 DOI: 10.1007/s13340-024-00727-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/16/2024] [Accepted: 04/24/2024] [Indexed: 10/30/2024]
Abstract
Genome-wide association studies (GWAS) have significantly advanced the identification of genetic susceptibility variants associated with complex diseases. As of 2023, approximately 800 variants predisposing individuals to the risk of type 2 diabetes (T2D) were identified through GWAS, and the majority of studies were predominantly conducted in European populations. Despite the shared nature of the majority of genetic susceptibility loci across diverse ethnic populations, GWAS in non-European populations, including Japanese and East Asian populations, have revealed population-specific T2D loci. Currently, polygenic risk scores (PRSs), encompassing millions of associated variants, can identify individuals with a higher T2D risk than the general population. However, GWAS focusing on microvascular complications of diabetes have identified a limited number of disease-susceptibility loci. Ongoing efforts are crucial to enhance the applicability of PRS for all ethnic groups and unravel the genetic architecture of microvascular complications of diabetes.
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Affiliation(s)
- Minako Imamura
- Department of Advanced Genomic and Laboratory Medicine, Graduate School of Medicine, University of the Ryukyus, Nishihara-Cho, Okinawa 903-0215 Japan
- Division of Clinical Laboratory and Blood Transfusion, University of the Ryukyus Hospital, Nishihara-Cho, Okinawa 930-0215 Japan
| | - Shiro Maeda
- Department of Advanced Genomic and Laboratory Medicine, Graduate School of Medicine, University of the Ryukyus, Nishihara-Cho, Okinawa 903-0215 Japan
- Division of Clinical Laboratory and Blood Transfusion, University of the Ryukyus Hospital, Nishihara-Cho, Okinawa 930-0215 Japan
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Sekar P, Aji AS, Ariyasra U, Sari SR, Tasrif N, Yani FF, Lovegrove JA, Sudji IR, Lipoeto NI, Vimaleswaran KS. A Novel Interaction between a 23-SNP Genetic Risk Score and Monounsaturated Fatty Acid Intake on HbA1c Levels in Southeast Asian Women. Nutrients 2024; 16:3022. [PMID: 39275336 PMCID: PMC11397529 DOI: 10.3390/nu16173022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2024] [Revised: 08/21/2024] [Accepted: 08/29/2024] [Indexed: 09/16/2024] Open
Abstract
Metabolic diseases result from interactions between genetic and lifestyle factors. Understanding the combined influences of single-nucleotide polymorphisms (SNPs) and lifestyle is crucial. This study employs genetic risk scores (GRS) to assess SNPs, providing insight beyond single gene/SNP studies by revealing synergistic effects. Here, we aim to investigate the association of a 23-SNP GRS with metabolic disease-related traits (obesity and type 2 diabetes) to understand if these associations are altered by lifestyle/dietary factors. For this study, 106 Minangkabau women were included and underwent physical, anthropometric, biochemical, dietary and genetic evaluations. The interaction of GRS with lifestyle factors was analyzed using linear regression models, adjusting for potential confounders. No statistically significant associations were observed between GRS and metabolic traits; however, this study demonstrates a novel interaction observed between 13-SNP GRS and monounsaturated fatty acid (MUFA) intake, and that it had an effect on HbA1c levels (p = 0.026). Minangkabau women with low MUFA intake (≤7.0 g/day) and >13 risk alleles had significantly higher HbA1c levels (p = 0.010). This finding has implications for public health, suggesting the need for large-scale studies to confirm our results before implementing dietary interventions in the Indonesian population. Identifying genetic influences on dietary response can inform personalized nutrition strategies to reduce the risk of metabolic disease.
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Affiliation(s)
- Padmini Sekar
- Hugh Sinclair Unit of Human Nutrition, Department of Food and Nutritional Sciences, Institute for Cardiovascular and Metabolic Research (ICMR), University of Reading, Reading RG6 6DZ, UK
| | - Arif S Aji
- Department of Nutrition, Faculty of Health Sciences, Alma Ata University, Bantul, Yogyakarta 55183, Indonesia
| | - Utami Ariyasra
- Department of Biomedical Science, Faculty of Medicine, Andalas University, Padang 25163, Indonesia
| | - Sri R Sari
- Department of Biomedical Science, Faculty of Medicine, Andalas University, Padang 25163, Indonesia
| | - Nabila Tasrif
- Culinary Study Program, Faculty of Tourism and Hospitality, Universitas Negeri Padang, Padang 25163, Indonesia
| | - Finny F Yani
- Department of Child Health, Faculty of Medicine, Andalas University, Padang 25163, Indonesia
| | - Julie A Lovegrove
- Hugh Sinclair Unit of Human Nutrition, Department of Food and Nutritional Sciences, Institute for Cardiovascular and Metabolic Research (ICMR), University of Reading, Reading RG6 6DZ, UK
| | - Ikhwan R Sudji
- Biomedical Laboratory, Faculty of Medicine, Andalas University, Padang 25163, Indonesia
| | - Nur I Lipoeto
- Department of Nutrition, Faculty of Medicine, Andalas University, Padang 25163, Indonesia
| | - Karani S Vimaleswaran
- Hugh Sinclair Unit of Human Nutrition, Department of Food and Nutritional Sciences, Institute for Cardiovascular and Metabolic Research (ICMR), University of Reading, Reading RG6 6DZ, UK
- Institute for Food, Nutrition and Health (IFNH), University of Reading, Reading RG6 6AH, UK
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Bouchi R, Kondo T, Ohta Y, Goto A, Tanaka D, Satoh H, Yabe D, Nishimura R, Harada N, Kamiya H, Suzuki R, Yamauchi T. A consensus statement from the Japan Diabetes Society: A proposed algorithm for pharmacotherapy in people with type 2 diabetes - 2nd edition (English version). J Diabetes Investig 2024; 15:1326-1342. [PMID: 38988282 PMCID: PMC11363114 DOI: 10.1111/jdi.14202] [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: 03/12/2024] [Revised: 03/12/2024] [Accepted: 03/13/2024] [Indexed: 07/12/2024] Open
Abstract
This algorithm was issued for the appropriate use of drugs for the treatment of type 2 diabetes mellitus in Japan. The revisions include safety considerations, fatty liver disease as a comorbidity to be taken into account and the position of tirzepatide.
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Affiliation(s)
- Ryotaro Bouchi
- Diabetes and Metabolism Information Center, Diabetes Research CenterNational Center for Global Health and MedicineTokyoJapan
| | - Tatsuya Kondo
- Department of Diabetes, Metabolism and EndocrinologyKumamoto University HospitalKumamotoJapan
| | - Yasuharu Ohta
- Division of Endocrinology, Metabolism, Hematological Sciences and TherapeuticsYamaguchi University Graduate School of MedicineYamaguchiJapan
| | - Atsushi Goto
- Department of Health Data Science, Graduate School of Data ScienceYokohama City UniversityYokohamaJapan
| | - Daisuke Tanaka
- Department of Diabetes, Endocrinology and Nutrition, Graduate School of MedicineKyoto UniversityKyotoJapan
| | - Hiroaki Satoh
- Department of Diabetes and EndocrinologyJuntendo University Urayasu HospitalChibaJapan
| | - Daisuke Yabe
- Department of Diabetes, Endocrinology and Metabolism and Department of Rheumatology and Clinical ImmunologyGifu University Graduate School of MedicineGifuJapan
| | - Rimei Nishimura
- Division of Diabetes, Metabolism and EndocrinologyJikei University School of MedicineTokyoJapan
| | - Norio Harada
- Department of Diabetes, Endocrinology and Nutrition, Graduate School of MedicineKyoto UniversityKyotoJapan
| | - Hideki Kamiya
- Division of Diabetes, Department of Internal MedicineAichi Medical UniversityNagakuteJapan
| | - Ryo Suzuki
- Department of Diabetes, Metabolism and EndocrinologyTokyo Medical UniversityTokyoJapan
| | - Toshimasa Yamauchi
- Department of Diabetes and Metabolic DiseasesUniversity of Tokyo Graduate School of MedicineTokyoJapan
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11
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Gupta MK, Gouda G, Vadde R. Relation Between Obesity and Type 2 Diabetes: Evolutionary Insights, Perspectives and Controversies. Curr Obes Rep 2024; 13:475-495. [PMID: 38850502 DOI: 10.1007/s13679-024-00572-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 05/13/2024] [Indexed: 06/10/2024]
Abstract
PURPOSE OF REVIEW Since the mid-twentieth century, obesity and its related comorbidities, notably insulin resistance (IR) and type 2 diabetes (T2D), have surged. Nevertheless, their underlying mechanisms remain elusive. Evolutionary medicine (EM) sheds light on these issues by examining how evolutionary processes shape traits and diseases, offering insights for medical practice. This review summarizes the pathogenesis and genetics of obesity-related IR and T2D. Subsequently, delving into their evolutionary connections. Addressing limitations and proposing future research directions aims to enhance our understanding of these conditions, paving the way for improved treatments and prevention strategies. RECENT FINDINGS Several evolutionary hypotheses have been proposed to unmask the origin of obesity-related IR and T2D, e.g., the "thrifty genotype" hypothesis suggests that certain "thrifty genes" that helped hunter-gatherer populations efficiently store energy as fat during feast-famine cycles are now maladaptive in our modern obesogenic environment. The "drifty genotype" theory suggests that if thrifty genes were advantageous, they would have spread widely, but proposes genetic drift instead. The "behavioral switch" and "carnivore connection" hypotheses propose insulin resistance as an adaptation for a brain-dependent, low-carbohydrate lifestyle. The thrifty phenotype theory suggests various metabolic outcomes shaped by genes and environment during development. However, the majority of these hypotheses lack experimental validation. Understanding why ancestral advantages now predispose us to diseases may aid in drug development and prevention of disease. EM helps us to understand the evolutionary relation between obesity-related IR and T2D. But still gaps and contradictions persist. Further interdisciplinary research is required to elucidate complete mechanisms.
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Affiliation(s)
- Manoj Kumar Gupta
- Department of Biotechnology & Bioinformatics, Yogi Vemana University, Kadapa, 516005, Andhra Pradesh, India.
| | - Gayatri Gouda
- ICAR-National Rice Research Institute, Cuttack, 753 006, Odisha, India
| | - Ramakrishna Vadde
- Department of Biotechnology & Bioinformatics, Yogi Vemana University, Kadapa, 516005, Andhra Pradesh, India
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12
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Díaz-García JD, Leyva-Leyva M, Sánchez-Aguillón F, de León-Bautista MP, Fuentes-Venegas A, Torres-Viloria A, Tenorio-Aguirre EK, Morales-Lázaro SL, Olivo-Díaz A, González-Ramírez R. Association Study of CACNA1D, KCNJ11, KCNQ1, and CACNA1E Single-Nucleotide Polymorphisms with Type 2 Diabetes Mellitus. Int J Mol Sci 2024; 25:9196. [PMID: 39273144 PMCID: PMC11395491 DOI: 10.3390/ijms25179196] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2024] [Revised: 08/16/2024] [Accepted: 08/22/2024] [Indexed: 09/15/2024] Open
Abstract
Type 2 diabetes mellitus (T2DM) is a complex chronic disease characterized by decreased insulin secretion and the development of insulin resistance. Previous genome-wide association studies demonstrated that single-nucleotide polymorphisms (SNPs) present in genes coding for ion channels involved in insulin secretion increase the risk of developing this disease. We determined the association of 16 SNPs found in CACNA1D, KCNQ1, KCNJ11, and CACNA1E genes and the increased probability of developing T2DM. In this work, we performed a case-control study in 301 Mexican adults, including 201 cases with diabetes and 100 controls without diabetes. Our findings indicate a moderate association between T2DM and the C allele, and the C/C genotype of rs312480 within CACNA1D. The CAG haplotype surprisingly showed a protective effect, whereas the CAC and CGG haplotypes have a strong association with T2DM. The C allele and C/C genotype of rs5219 were significantly associated with diabetes. Also, an association was observed between diabetes and the A allele and the A/A genotype of rs3753737 and rs175338 in CACNA1E. The TGG and CGA haplotypes were also found to be significantly associated. The findings of this study indicate that the SNPs examined could serve as a potential diagnostic tool and contribute to the susceptibility of the Mexican population to this disease.
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Affiliation(s)
- Juan Daniel Díaz-García
- División de Medicina Interna, Hospital General “Dr. Manuel Gea González”, Mexico City 14080, Mexico; (J.D.D.-G.); (A.F.-V.); (A.T.-V.); (E.K.T.-A.)
| | - Margarita Leyva-Leyva
- Departamento de Biología Molecular e Histocompatibilidad, Hospital General “Dr. Manuel Gea González”, Mexico City 14080, Mexico; (M.L.-L.); (F.S.-A.); (A.O.-D.)
| | - Fabiola Sánchez-Aguillón
- Departamento de Biología Molecular e Histocompatibilidad, Hospital General “Dr. Manuel Gea González”, Mexico City 14080, Mexico; (M.L.-L.); (F.S.-A.); (A.O.-D.)
| | - Mercedes Piedad de León-Bautista
- Escuela de Medicina, Universidad Vasco de Quiroga, Morelia 58090, Mexico;
- Laboratorio de Enfermedades Infecciosas y Genómica (INEX LAB), Morelia 58280, Mexico
| | - Abel Fuentes-Venegas
- División de Medicina Interna, Hospital General “Dr. Manuel Gea González”, Mexico City 14080, Mexico; (J.D.D.-G.); (A.F.-V.); (A.T.-V.); (E.K.T.-A.)
| | - Alfredo Torres-Viloria
- División de Medicina Interna, Hospital General “Dr. Manuel Gea González”, Mexico City 14080, Mexico; (J.D.D.-G.); (A.F.-V.); (A.T.-V.); (E.K.T.-A.)
| | - Erika Karina Tenorio-Aguirre
- División de Medicina Interna, Hospital General “Dr. Manuel Gea González”, Mexico City 14080, Mexico; (J.D.D.-G.); (A.F.-V.); (A.T.-V.); (E.K.T.-A.)
| | - Sara Luz Morales-Lázaro
- División de Neurociencias, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, Mexico City 04510, Mexico;
- Centro de Investigación Sobre el Envejecimiento, CINVESTAV, Mexico City 14330, Mexico
| | - Angélica Olivo-Díaz
- Departamento de Biología Molecular e Histocompatibilidad, Hospital General “Dr. Manuel Gea González”, Mexico City 14080, Mexico; (M.L.-L.); (F.S.-A.); (A.O.-D.)
| | - Ricardo González-Ramírez
- Departamento de Biología Molecular e Histocompatibilidad, Hospital General “Dr. Manuel Gea González”, Mexico City 14080, Mexico; (M.L.-L.); (F.S.-A.); (A.O.-D.)
- Centro de Investigación Sobre el Envejecimiento, CINVESTAV, Mexico City 14330, Mexico
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13
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Zhou Z, Gong M, Pande A, Margineanu A, Lisewski U, Purfürst B, Zhu H, Liang L, Jia S, Froehler S, Zeng C, Kühnen P, Khodaverdi S, Krill W, Röpke T, Chen W, Raile K, Sander M, Izsvák Z. Atypical KCNQ1/Kv7 channel function in a neonatal diabetes patient: Hypersecretion preceded the failure of pancreatic β-cells. iScience 2024; 27:110291. [PMID: 39055936 PMCID: PMC11269803 DOI: 10.1016/j.isci.2024.110291] [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: 02/29/2024] [Revised: 05/07/2024] [Accepted: 06/14/2024] [Indexed: 07/28/2024] Open
Abstract
KCNQ1/Kv7, a low-voltage-gated K+ channel, regulates cardiac rhythm and glucose homeostasis. While KCNQ1 mutations are associated with long-QT syndrome and type2 diabetes, its function in human pancreatic cells remains controversial. We identified a homozygous KCNQ1 mutation (R397W) in an individual with permanent neonatal diabetes melitus (PNDM) without cardiovascular symptoms. To decipher the potential mechanism(s), we introduced the mutation into human embryonic stem cells and generated islet-like organoids (SC-islets) using CRISPR-mediated homology-repair. The mutation did not affect pancreatic differentiation, but affected channel function by increasing spike frequency and Ca2+ flux, leading to insulin hypersecretion. With prolonged culturing, the mutant islets decreased their secretion and gradually deteriorated, modeling a diabetic state, which accelerated by high glucose levels. The molecular basis was the downregulated expression of voltage-activated Ca2+ channels and oxidative phosphorylation. Our study provides a better understanding of the role of KCNQ1 in regulating insulin secretion and β-cell survival in hereditary diabetes pathology.
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Affiliation(s)
- Zhimin Zhou
- Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), 13125 Berlin, Germany
| | - Maolian Gong
- Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), 13125 Berlin, Germany
| | - Amit Pande
- Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), 13125 Berlin, Germany
| | - Anca Margineanu
- Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), 13125 Berlin, Germany
| | - Ulrike Lisewski
- Experimental and Clinical Research Center (ECRC) of the MDC and Charité Berlin, 13125 Berlin, Germany
| | - Bettina Purfürst
- Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), 13125 Berlin, Germany
| | - Han Zhu
- Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA, USA
- Department of Pediatrics, University of California San Diego, La Jolla, CA 92037, USA
| | - Lei Liang
- Department of Pediatrics, Anhui Provincial Children’s Hospital, Hefei 23000, China
| | - Shiqi Jia
- The First Affiliated Hospital of Jinan University, Guangzhou 510000, China
| | - Sebastian Froehler
- Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), 13125 Berlin, Germany
| | - Chun Zeng
- Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA, USA
- Department of Pediatrics, University of California San Diego, La Jolla, CA 92037, USA
| | - Peter Kühnen
- Charité, Universitätsmedizin Berlin, Virchow-Klinikum, 13125 Berlin, Germany
| | | | - Winfried Krill
- Department of Pediatrics, Klinikum Hanau, 63450 Hanau, Germany
| | - Torsten Röpke
- Experimental and Clinical Research Center (ECRC) of the MDC and Charité Berlin, 13125 Berlin, Germany
| | - Wei Chen
- Department of Biology, Southern University of Science and Technology, Shenzhen 518000, China
| | - Klemens Raile
- Charité, Universitätsmedizin Berlin, Virchow-Klinikum, 13125 Berlin, Germany
| | - Maike Sander
- Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), 13125 Berlin, Germany
- Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA, USA
- Department of Pediatrics, University of California San Diego, La Jolla, CA 92037, USA
| | - Zsuzsanna Izsvák
- Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), 13125 Berlin, Germany
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14
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Guo J, Zhang C, Zhao H, Yan Y, Liu Z. The key mediator of diabetic kidney disease: Potassium channel dysfunction. Genes Dis 2024; 11:101119. [PMID: 38523672 PMCID: PMC10958065 DOI: 10.1016/j.gendis.2023.101119] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2021] [Revised: 06/11/2022] [Accepted: 06/04/2023] [Indexed: 03/26/2024] Open
Abstract
Diabetic kidney disease is a leading cause of end-stage renal disease, making it a global public health concern. The molecular mechanisms underlying diabetic kidney disease have not been elucidated due to its complex pathogenesis. Thus, exploring these mechanisms from new perspectives is the current focus of research concerning diabetic kidney disease. Ion channels are important proteins that maintain the physiological functions of cells and organs. Among ion channels, potassium channels stand out, because they are the most common and important channels on eukaryotic cell surfaces and function as the basis for cell excitability. Certain potassium channel abnormalities have been found to be closely related to diabetic kidney disease progression and genetic susceptibility, such as KATP, KCa, Kir, and KV. In this review, we summarized the roles of different types of potassium channels in the occurrence and development of diabetic kidney disease to discuss whether the development of DKD is due to potassium channel dysfunction and present new ideas for the treatment of DKD.
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Affiliation(s)
- Jia Guo
- Nephrology Research Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
- Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Zhengzhou, Henan 450052, China
- Research Center for Kidney Disease, Zhengzhou, Henan 450052, China
| | - Chaojie Zhang
- Nephrology Research Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
- Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Zhengzhou, Henan 450052, China
- Research Center for Kidney Disease, Zhengzhou, Henan 450052, China
| | - Hui Zhao
- Nephrology Research Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
- Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Zhengzhou, Henan 450052, China
- Research Center for Kidney Disease, Zhengzhou, Henan 450052, China
| | - Yufan Yan
- Nephrology Research Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
- Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Zhengzhou, Henan 450052, China
- Research Center for Kidney Disease, Zhengzhou, Henan 450052, China
| | - Zhangsuo Liu
- Nephrology Research Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
- Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Zhengzhou, Henan 450052, China
- Research Center for Kidney Disease, Zhengzhou, Henan 450052, China
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15
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Bouchi R, Kondo T, Ohta Y, Goto A, Tanaka D, Satoh H, Yabe D, Nishimura R, Harada N, Kamiya H, Suzuki R, Yamauchi T. A consensus statement from the Japan Diabetes Society (JDS): a proposed algorithm for pharmacotherapy in people with type 2 diabetes-2nd Edition (English version). Diabetol Int 2024; 15:327-345. [PMID: 39101173 PMCID: PMC11291844 DOI: 10.1007/s13340-024-00723-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/25/2024] [Accepted: 02/08/2024] [Indexed: 08/06/2024]
Abstract
The Japan Diabetes Society (JDS) adopted a sweeping decision to release consensus statements on relevant issues in diabetes management that require updating from time to time and launched a "JDS Committee on Consensus Statement Development." In March 2020, the committee's first consensus statement on "Medical Nutrition Therapy and Dietary Counseling for People with Diabetes" was published. In September 2022, a second consensus "algorithm for pharmacotherapy in people with type 2 diabetes" was proposed. In developing an algorithm for diabetes pharmacotherapy in people with type 2 diabetes, the working concept was that priority should be given to selecting such medications as would appropriately address the diabetes pathology in each patient while simultaneously weighing the available evidence for these medications and the prescribing patterns in clinical practice in Japan. These consensus statements are intended to present the committee's take on diabetes management in Japan, based on the evidence currently available for each of the issues addressed. It is thus hoped that practicing diabetologists will not fail to consult these statements to provide the best available practice in their respective clinical settings. Given that the persistent dual GIP/GLP-1 receptor agonist tirzepatide was approved in April 2023, these consensus statements have been revised1). In this revision, specifically, tirzepatide was added to the end of [likely involving insulin resistance] of "Obese patients" in Step 1: "Select medications to address the diabetes pathology involved" in Fig. 2. While the sentence, "Insulin insufficiency and resistance can be assessed by referring to the various indices listed in the JDS 'Guide to Diabetes Management.' was mentioned in the previous edition as well, "While insulin resistance is analogized based on BMI, abdominal obesity, and visceral fat accumulation, an assessment of indicators (e.g., HOMA-IR) is desirable" was added as information in order to more accurately recognize the pathology. Regarding Step 2: "Give due consideration to safety," "For renal excretion" was added to the "Rule of thumb 2: Avoid glinides in patients with renal impairment." The order of the medications in "rule of thumb 3: Avoid thiazolidinediones and biguanides in patients with heart failure (in whom they are contraindicated)." to thiazolidinediones then biguanides. In the description of the lowest part of Fig. 2, for each patient failing to achieve his/her HbA1c control goal, "while reverting to step 1" was changed to "while reverting to the opening" and "including reassessment if the patient is indicated for insulin therapy" was added. In the separate table, the column for tirzepatides was added, while the two items, "Characteristic side effects" and "Persistence of effect" were added to the area of interest. The revision also carried additional descriptions of the figure and table such as tirzepatides and "Characteristic side effects" in the statement, and while not mentioned in the proposed algorithm figure, nonalcoholic fatty liver disease (NAFLD) is covered from this revision for patients with comorbidities calling for medical attention. Moreover, detailed information was added to the relative/absolute indication for insulin therapy, the Kumamoto Declaration 2013 for glycemic targets, and glycemic targets for older people with diabetes. Again, in this revision, it is hoped that the algorithm presented here will not only contribute to improved diabetes management in Japan, but will continue to evolve into a better algorithm over time, reflecting new evidence as it becomes available.
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Affiliation(s)
- Ryotaro Bouchi
- Diabetes and Metabolism Information Center, Diabetes Research Center, National Center for Global Health and Medicine, Tokyo, Japan
| | - Tatsuya Kondo
- Department of Diabetes, Metabolism and Endocrinology, Kumamoto University Hospital, Kumamoto, Japan
| | - Yasuharu Ohta
- Division of Endocrinology, Metabolism, Hematological Sciences and Therapeutics, Yamaguchi University Graduate School of Medicine, Yamaguchi, Japan
| | - Atsushi Goto
- Department of Health Data Science, Graduate School of Data Science, Yokohama City University, Kanagawa, Japan
| | - Daisuke Tanaka
- Department of Diabetes, Endocrinology and Nutrition, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Hiroaki Satoh
- Department of Diabetes and Endocrinology, Juntendo University Urayasu Hospital, Chiba, Japan
| | - Daisuke Yabe
- Department of Diabetes, Endocrinology and Metabolism and Department of Rheumatology and Clinical Immunology, Gifu University Graduate School of Medicine, Gifu, Japan
| | - Rimei Nishimura
- Division of Diabetes, Metabolism and Endocrinology, Jikei University School of Medicine, Tokyo, Japan
| | - Norio Harada
- Department of Diabetes, Endocrinology and Nutrition, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Hideki Kamiya
- Division of Diabetes, Department of Internal Medicine, Aichi Medical University, Aichi, Japan
| | - Ryo Suzuki
- Department of Diabetes, Metabolism and Endocrinology, Tokyo Medical University, Tokyo, Japan
| | - Toshimasa Yamauchi
- Department of Diabetes and Metabolic Diseases, University of Tokyo Graduate School of Medicine, Tokyo, Japan
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16
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Stankevic E, Kern T, Borisevich D, Poulsen CS, Madsen AL, Hansen TH, Jonsson A, Schubert M, Nygaard N, Nielsen T, Belstrøm D, Ahluwalia TS, Witte DR, Grarup N, Arumugam M, Pedersen O, Hansen T. Genome-wide association study identifies host genetic variants influencing oral microbiota diversity and metabolic health. Sci Rep 2024; 14:14738. [PMID: 38926497 PMCID: PMC11208528 DOI: 10.1038/s41598-024-65538-8] [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: 03/13/2024] [Accepted: 06/20/2024] [Indexed: 06/28/2024] Open
Abstract
The microbial communities of the oral cavity are important elements of oral and systemic health. With emerging evidence highlighting the heritability of oral bacterial microbiota, this study aimed to identify host genome variants that influence oral microbial traits. Using data from 16S rRNA gene amplicon sequencing, we performed genome-wide association studies with univariate and multivariate traits of the salivary microbiota from 610 unrelated adults from the Danish ADDITION-PRO cohort. We identified six single nucleotide polymorphisms (SNPs) in human genomes that showed associations with abundance of bacterial taxa at different taxonomical tiers (P < 5 × 10-8). Notably, SNP rs17793860 surpassed our study-wide significance threshold (P < 1.19 × 10-9). Additionally, rs4530093 was linked to bacterial beta diversity (P < 5 × 10-8). Out of these seven SNPs identified, six exerted effects on metabolic traits, including glycated hemoglobin A1c, triglyceride and high-density lipoprotein cholesterol levels, the risk of type 2 diabetes and stroke. Our findings highlight the impact of specific host SNPs on the composition and diversity of the oral bacterial community. Importantly, our results indicate an intricate interplay between host genetics, the oral microbiota, and metabolic health. We emphasize the need for integrative approaches considering genetic, microbial, and metabolic factors.
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Affiliation(s)
- Evelina Stankevic
- The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Timo Kern
- The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Dmitrii Borisevich
- The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Casper Sahl Poulsen
- The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Anne Lundager Madsen
- The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Tue Haldor Hansen
- The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Medical Department, Zealand University Hospital, Koege, Denmark
| | - Anna Jonsson
- The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Mikkel Schubert
- The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Nikoline Nygaard
- Department of Odontology, Section for Clinical Oral Microbiology, University of Copenhagen, Copenhagen, Denmark
| | - Trine Nielsen
- The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Medical Department, Zealand University Hospital, Koege, Denmark
- Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
| | - Daniel Belstrøm
- Department of Odontology, Section for Clinical Oral Microbiology, University of Copenhagen, Copenhagen, Denmark
| | - Tarunveer S Ahluwalia
- Steno Diabetes Center Copenhagen, Herlev, Denmark
- The Bioinformatics Center, Department of Biology, University of Copenhagen, Copenhagen, Denmark
| | - Daniel R Witte
- Department of Public Health, Aarhus University, Aarhus, Denmark
- Steno Diabetes Center Aarhus, Aarhus, Denmark
| | - Niels Grarup
- The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Manimozhiyan Arumugam
- The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Oluf Pedersen
- The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Center for Clinical Metabolic Research, Herlev-Gentofte University Hospital, Copenhagen, Denmark
| | - Torben Hansen
- The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
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17
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Ravi H, Das S, Devi Rajeswari V, Venkatraman G, Choudhury AA, Chakraborty S, Ramanathan G. Hormonal regulation in diabetes: Special emphasis on sex hormones and metabolic traits. ADVANCES IN PROTEIN CHEMISTRY AND STRUCTURAL BIOLOGY 2024; 142:257-291. [PMID: 39059988 DOI: 10.1016/bs.apcsb.2023.12.015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/28/2024]
Abstract
Diabetes constitutes a significant global public health challenge that is rapidly reaching epidemic proportions. Among the non-communicable diseases, the incidence of diabetes is rising at an alarming rate. The International Diabetes Federation has documented a 9.09% prevalence of diabetes among individuals aged between 20 and 79 years. The interplay of gonadal hormones and gender differences is critical in regulating insulin sensitivity and glucose tolerance, and this dynamic is particularly crucial because of the escalating incidence of diabetes. Variations in insulin sensitivity are observed across genders, levels of adiposity, and age groups. Both estrogen and testosterone are seen to influence glucose metabolism and insulin sensitivity. This chapter surveys the present knowledge of sex differences, sex hormones, and chromosomes on insulin imbalance and diabetes development. It further highlights the influence of metabolic traits in diabetes and changes in sex hormones during diabetic pregnancy. Notably, even stressful lifestyles have been acknowledged to induce hormonal imbalances. Furthermore, it discusses the potential of hormonal therapy to help stabilize sex hormones in diabetic individuals and focuses on the most recent research investigating the correlation between sex hormones and diabetes.
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Affiliation(s)
- Harini Ravi
- Department of Bio-Medical Sciences, School of Bio Sciences and Technology, Vellore Institute of Technology (VIT), Vellore, Tamil Nadu, India
| | - Soumik Das
- Department of Bio-Medical Sciences, School of Bio Sciences and Technology, Vellore Institute of Technology (VIT), Vellore, Tamil Nadu, India
| | - V Devi Rajeswari
- Department of Bio-Medical Sciences, School of Bio Sciences and Technology, Vellore Institute of Technology (VIT), Vellore, Tamil Nadu, India
| | - Ganesh Venkatraman
- Department of Bio-Medical Sciences, School of Bio Sciences and Technology, Vellore Institute of Technology (VIT), Vellore, Tamil Nadu, India
| | - Abbas Alam Choudhury
- Department of Bio-Medical Sciences, School of Bio Sciences and Technology, Vellore Institute of Technology (VIT), Vellore, Tamil Nadu, India
| | - Shreya Chakraborty
- Department of Bio-Medical Sciences, School of Bio Sciences and Technology, Vellore Institute of Technology (VIT), Vellore, Tamil Nadu, India
| | - Gnanasambandan Ramanathan
- Department of Bio-Medical Sciences, School of Bio Sciences and Technology, Vellore Institute of Technology (VIT), Vellore, Tamil Nadu, India.
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18
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Nadiger N, Veed JK, Chinya Nataraj P, Mukhopadhyay A. DNA methylation and type 2 diabetes: a systematic review. Clin Epigenetics 2024; 16:67. [PMID: 38755631 PMCID: PMC11100087 DOI: 10.1186/s13148-024-01670-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2024] [Accepted: 04/11/2024] [Indexed: 05/18/2024] Open
Abstract
OBJECTIVE DNA methylation influences gene expression and function in the pathophysiology of type 2 diabetes mellitus (T2DM). Mapping of T2DM-associated DNA methylation could aid early detection and/or therapeutic treatment options for diabetics. DESIGN A systematic literature search for associations between T2DM and DNA methylation was performed. Prospero registration ID: CRD42020140436. METHODS PubMed and ScienceDirect databases were searched (till October 19, 2023). Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and New Castle Ottawa scale were used for reporting the selection and quality of the studies, respectively. RESULT Thirty-two articles were selected. Four of 130 differentially methylated genes in blood, adipose, liver or pancreatic islets (TXNIP, ABCG1, PPARGC1A, PTPRN2) were reported in > 1 study. TXNIP was hypomethylated in diabetic blood across ethnicities. Gene enrichment analysis of the differentially methylated genes highlighted relevant disease pathways (T2DM, type 1 diabetes and adipocytokine signaling). Three prospective studies reported association of methylation in IGFBP2, MSI2, FTO, TXNIP, SREBF1, PHOSPHO1, SOCS3 and ABCG1 in blood at baseline with incident T2DM/hyperglycemia. Sex-specific differential methylation was reported only for HOOK2 in visceral adipose tissue (female diabetics: hypermethylated, male diabetics: hypomethylated). Gene expression was inversely associated with methylation status in 8 studies, in genes including ABCG1 (blood), S100A4 (adipose tissue), PER2 (pancreatic islets), PDGFA (liver) and PPARGC1A (skeletal muscle). CONCLUSION This review summarizes available evidence for using DNA methylation patterns to unravel T2DM pathophysiology. Further validation studies in diverse populations will set the stage for utilizing this knowledge for identifying early diagnostic markers and novel druggable pathways.
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Affiliation(s)
- Nikhil Nadiger
- Research Scholar, Manipal Academy of Higher Education, Manipal, India
- Division of Nutrition, St. John's Research Institute, St. John's Medical College, St Johns National Academy of Health Sciences, Sarjapura Road, Koramangala, Bangalore, 560034, India
| | - Jyothisha Kana Veed
- Division of Nutrition, St. John's Research Institute, St. John's Medical College, St Johns National Academy of Health Sciences, Sarjapura Road, Koramangala, Bangalore, 560034, India
| | - Priyanka Chinya Nataraj
- Division of Nutrition, St. John's Research Institute, St. John's Medical College, St Johns National Academy of Health Sciences, Sarjapura Road, Koramangala, Bangalore, 560034, India
- Vedantu, Bangalore, India
| | - Arpita Mukhopadhyay
- Division of Nutrition, St. John's Research Institute, St. John's Medical College, St Johns National Academy of Health Sciences, Sarjapura Road, Koramangala, Bangalore, 560034, India.
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19
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Imamura M, Maeda S. Perspectives on genetic studies of type 2 diabetes from the genome-wide association studies era to precision medicine. J Diabetes Investig 2024; 15:410-422. [PMID: 38259175 PMCID: PMC10981147 DOI: 10.1111/jdi.14149] [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: 11/23/2023] [Revised: 12/24/2023] [Accepted: 01/04/2024] [Indexed: 01/24/2024] Open
Abstract
Genome-wide association studies (GWAS) have facilitated a substantial and rapid increase in the number of confirmed genetic susceptibility variants for complex diseases. Approximately 700 variants predisposing individuals to the risk for type 2 diabetes have been identified through GWAS until 2023. From 2018 to 2022, hundreds of type 2 diabetes susceptibility loci with smaller effect sizes were identified through large-scale GWAS with sample sizes of 200,000 to >1 million. The clinical translation of genetic information for type 2 diabetes includes the development of novel therapeutics and risk predictions. Although drug discovery based on loci identified in GWAS remains challenging owing to the difficulty of functional annotation, global efforts have been made to identify novel biological mechanisms and therapeutic targets by applying multi-omics approaches or searching for disease-associated coding variants in isolated founder populations. Polygenic risk scores (PRSs), comprising up to millions of associated variants, can identify individuals with higher disease risk than those in the general population. In populations of European descent, PRSs constructed from base GWAS data with a sample size of approximately 450,000 have predicted the onset of diseases well. However, European GWAS-derived PRSs have limited predictive performance in non-European populations. The predictive accuracy of a PRS largely depends on the sample size of the base GWAS data. The results of GWAS meta-analyses for multi-ethnic groups as base GWAS data and cross-population polygenic prediction methodology have been applied to establish a universal PRS applicable to small isolated ethnic populations.
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Affiliation(s)
- Minako Imamura
- Department of Advanced Genomic and Laboratory Medicine, Graduate School of MedicineUniversity of the RyukyusNishihara‐ChoJapan
- Division of Clinical Laboratory and Blood TransfusionUniversity of the Ryukyus HospitalNishihara‐ChoJapan
| | - Shiro Maeda
- Department of Advanced Genomic and Laboratory Medicine, Graduate School of MedicineUniversity of the RyukyusNishihara‐ChoJapan
- Division of Clinical Laboratory and Blood TransfusionUniversity of the Ryukyus HospitalNishihara‐ChoJapan
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Li DX, Yin LP, Song YQ, Shao NN, Zhu H, He CS, Sun JJ. KCNQ1 rs2237895 gene polymorphism increases susceptibility to type 2 diabetes mellitus in Asian populations. World J Diabetes 2024; 15:552-564. [PMID: 38591089 PMCID: PMC10999049 DOI: 10.4239/wjd.v15.i3.552] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/25/2023] [Revised: 12/13/2023] [Accepted: 02/02/2024] [Indexed: 03/15/2024] Open
Abstract
BACKGROUND The association of single nucleotide polymorphism of KCNQ1 gene rs2237895 with type 2 diabetes mellitus (T2DM) is currently controversial. It is unknown whether this association can be gene realized across different populations. AIM To determine the association of KCNQ1 rs2237895 with T2DM and provide reliable evidence for genetic susceptibility to T2DM. METHODS We searched PubMed, Embase, Web of Science, Cochrane Library, Medline, Baidu Academic, China National Knowledge Infrastructure, China Biomedical Liter-ature Database, and Wanfang to investigate the association between KCNQ1 gene rs2237895 and the risk of T2DM up to January 12, 2022. Review Manager 5.4 was used to analyze the association of the KCNQ1 gene rs2237895 polymorphism with T2DM and to evaluate the publication bias of the selected literature. RESULTS Twelve case-control studies (including 11273 cases and 11654 controls) met our inclusion criteria. In the full population, allelic model [odds ratio (OR): 1.19; 95% confidence interval (95%CI): 1.09-1.29; P < 0.0001], recessive model (OR: 1.20; 95%CI: 1.11-1.29; P < 0.0001), dominant model (OR: 1.27. 95%CI: 1.14-1.42; P < 0.0001), and codominant model (OR: 1.36; 95%CI: 1.15-1.60; P = 0.0003) (OR: 1.22; 95%CI: 1.10-1.36; P = 0.0002) indicated that the KCNQ1 gene rs2237895 polymorphism was significantly correlated with susceptibility to T2DM. In stratified analysis, this association was confirmed in Asian populations: allelic model (OR: 1.25; 95%CI: 1.13-1.37; P < 0.0001), recessive model (OR: 1.29; 95%CI: 1.11-1.49; P = 0.0007), dominant model (OR: 1.35; 95%CI: 1.20-1.52; P < 0.0001), codominant model (OR: 1.49; 95%CI: 1.22-1.81; P < 0.0001) (OR: 1.26; 95%CI: 1.16-1.36; P < 0.0001). In non-Asian populations, this association was not significant: Allelic model (OR: 1.06, 95%CI: 0.98-1.14; P = 0.12), recessive model (OR: 1.04; 95%CI: 0.75-1.42; P = 0.83), dominant model (OR: 1.06; 95%CI: 0.98-1.15; P = 0.15), codominant model (OR: 1.08; 95%CI: 0.82-1.42; P = 0.60. OR: 1.15; 95%CI: 0.95-1.39; P = 0.14). CONCLUSION KCNQ1 gene rs2237895 was significantly associated with susceptibility to T2DM in an Asian population. Carriers of the C allele had a higher risk of T2DM. This association was not significant in non-Asian populations.
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Affiliation(s)
- Dong-Xu Li
- First Clinical Medical College, Anhui Medical University, Hefei 230032, Anhui Province, China
| | - Li-Ping Yin
- School of Mental Health and Psychological Sciences, Anhui Medical University, Hefei 230032, Anhui Province, China
| | - Yu-Qi Song
- First Clinical Medical College, Anhui Medical University, Hefei 230032, Anhui Province, China
| | - Nan-Nan Shao
- School of Clinical Medicine, Anhui Medical University, Hefei 230031, Anhui Province, China
| | - Huan Zhu
- First Clinical Medical College, Anhui Medical University, Hefei 230032, Anhui Province, China
| | - Chen-Sen He
- School of Mental Health and Psychological Sciences, Anhui Medical University, Hefei 230032, Anhui Province, China
| | - Jiang-Jie Sun
- School of Health Care Management, Anhui Medical University, Hefei 230032, Anhui Province, China
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Sakurai Y, Kubota N, Takamoto I, Wada N, Aihara M, Hayashi T, Kubota T, Hiraike Y, Sasako T, Nakao H, Aiba A, Chikaoka Y, Kawamura T, Kadowaki T, Yamauchi T. Overexpression of UBE2E2 in Mouse Pancreatic β-Cells Leads to Glucose Intolerance via Reduction of β-Cell Mass. Diabetes 2024; 73:474-489. [PMID: 38064504 DOI: 10.2337/db23-0150] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/22/2023] [Accepted: 12/03/2023] [Indexed: 02/22/2024]
Abstract
Genome-wide association studies have identified several gene polymorphisms, including UBE2E2, associated with type 2 diabetes. Although UBE2E2 is one of the ubiquitin-conjugating enzymes involved in the process of ubiquitin modifications, the pathophysiological roles of UBE2E2 in metabolic dysfunction are not yet understood. Here, we showed upregulated UBE2E2 expression in the islets of a mouse model of diet-induced obesity. The diabetes risk allele of UBE2E2 (rs13094957) in noncoding regions was associated with upregulation of UBE2E2 mRNA in the human pancreas. Although glucose-stimulated insulin secretion was intact in the isolated islets, pancreatic β-cell-specific UBE2E2-transgenic (TG) mice exhibited reduced insulin secretion and decreased β-cell mass. In TG mice, suppressed proliferation of β-cells before the weaning period and while receiving a high-fat diet was accompanied by elevated gene expression levels of p21, resulting in decreased postnatal β-cell mass expansion and compensatory β-cell hyperplasia, respectively. In TG islets, proteomic analysis identified enhanced formation of various types of polyubiquitin chains, accompanied by increased expression of Nedd4 E3 ubiquitin protein ligase. Ubiquitination assays showed that UBE2E2 mediated the elongation of ubiquitin chains by Nedd4. The data suggest that UBE2E2-mediated ubiquitin modifications in β-cells play an important role in regulating glucose homeostasis and β-cell mass.
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Affiliation(s)
- Yoshitaka Sakurai
- Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, University of Tokyo, Tokyo, Japan
| | - Naoto Kubota
- Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, University of Tokyo, Tokyo, Japan
- Department of Metabolic Medicine, Faculty of Life Science, Kumamoto University, Kumamoto, Japan
- Clinical Nutrition Program, National Institutes of Biomedical Innovation, Health and Nutrition, Osaka, Japan
| | - Iseki Takamoto
- Department of Metabolism and Endocrinology, Ibaraki Medical Center, Tokyo Medical University, Tokyo, Japan
| | - Nobuhiro Wada
- Department of Anatomy I, School of Medicine, Sapporo Medical University, Sapporo, Japan
| | - Masakazu Aihara
- Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, University of Tokyo, Tokyo, Japan
| | - Takanori Hayashi
- Clinical Nutrition Program, National Institutes of Biomedical Innovation, Health and Nutrition, Osaka, Japan
| | - Tetsuya Kubota
- Clinical Nutrition Program, National Institutes of Biomedical Innovation, Health and Nutrition, Osaka, Japan
- Division of Diabetes and Metabolism, Institute of Medical Science, Asahi Life Foundation, Tokyo, Japan
| | - Yuta Hiraike
- Division for Health Service Promotion, The University of Tokyo, Tokyo, Japan
| | - Takayoshi Sasako
- Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, University of Tokyo, Tokyo, Japan
| | - Harumi Nakao
- Laboratory of Animal Resources, Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Atsu Aiba
- Laboratory of Animal Resources, Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Yoko Chikaoka
- Isotope Science Center, The University of Tokyo, Tokyo, Japan
| | | | | | - Toshimasa Yamauchi
- Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, University of Tokyo, Tokyo, Japan
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22
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Andargie TA, Mengistu B, Baffa LD, Gonete KA, Belew AK. Magnitude and predictors of pre-diabetes among adults in health facilities of Gondar city, Ethiopia: a cross-sectional study. Front Public Health 2023; 11:1164729. [PMID: 38162615 PMCID: PMC10754951 DOI: 10.3389/fpubh.2023.1164729] [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: 03/08/2023] [Accepted: 11/20/2023] [Indexed: 01/03/2024] Open
Abstract
Introduction Impaired glucose tolerance currently affects 374 million (7.5%) people worldwide, and by 2030, this number is predicted to affect 454 million (8%). Urban inhabitants have an increased risk of developing pre-diabetes. Thus, the study aimed to assess the magnitude of pre-diabetes and associated factors among adults attending outpatient departments of the health facilities of Gondar, Ethiopia. Method From 3 March to 18 April 2020, an institution-based cross-sectional study was conducted. A systematic random sampling technique was used to select 992 participants. Data were gathered using an interviewer-administered questionnaire, and fasting blood glucose was assessed using capillary blood. Bivariable and multivariable binary logistic regression analyses were fitted to check the association between independent variables and pre-diabetes. Statistical significance was declared at a level of P of <0.05. Results The prevalence of pre-diabetes was 16.6% (95% CIs: 14.3-18.8%). Age [AOR = 3.66, 95% CIs (2.05, 6.52)], a family history of diabetes mellitus [AOR = 3.46, 95% CIs (2.16, 5.52)], waist circumference [AOR = 3.6, 95% CIs (2.26, 5.88)], physical activity [AOR: 5.02, 95% CIs (2.87, 8.77)], dietary diversity [AOR = 3.07, 95% CIs (1.95, 4.84)], and smoking [AOR = 2.9, 95% CI (1.42, 6.05)] were factors associated with pre-diabetes. Conclusion From our study, we can conclude that one in six adults in the health facilities have pre-diabetes. Age, family history of diabetes, waist circumference, physical activity, dietary diversity, and smoking were the factors associated with pre-diabetes. Therefore, it is recommended that adults should be educated on modifying their lifestyle, including their diet, and substantial care should be provided for older adults.
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Affiliation(s)
| | - Berhanu Mengistu
- Department of Human Nutrition, Institute of Public Health, University of Gondar, Gondar, Ethiopia
| | - Lemlem Daniel Baffa
- Department of Human Nutrition, Institute of Public Health, University of Gondar, Gondar, Ethiopia
| | - Kedir Abdela Gonete
- Department of Human Nutrition, Institute of Public Health, University of Gondar, Gondar, Ethiopia
- Caring Futures Institute, College of Nursing and Health Sciences, Flinders University, Adelaide, South Australia
| | - Aysheshim Kassahun Belew
- Department of Human Nutrition, Institute of Public Health, University of Gondar, Gondar, Ethiopia
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Alam KA, Svalastoga P, Martinez A, Glennon JC, Haavik J. Potassium channels in behavioral brain disorders. Molecular mechanisms and therapeutic potential: A narrative review. Neurosci Biobehav Rev 2023; 152:105301. [PMID: 37414376 DOI: 10.1016/j.neubiorev.2023.105301] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2023] [Revised: 06/26/2023] [Accepted: 06/30/2023] [Indexed: 07/08/2023]
Abstract
Potassium channels (K+-channels) selectively control the passive flow of potassium ions across biological membranes and thereby also regulate membrane excitability. Genetic variants affecting many of the human K+-channels are well known causes of Mendelian disorders within cardiology, neurology, and endocrinology. K+-channels are also primary targets of many natural toxins from poisonous organisms and drugs used within cardiology and metabolism. As genetic tools are improving and larger clinical samples are being investigated, the spectrum of clinical phenotypes implicated in K+-channels dysfunction is rapidly expanding, notably within immunology, neurosciences, and metabolism. K+-channels that previously were considered to be expressed in only a few organs and to have discrete physiological functions, have recently been found in multiple tissues and with new, unexpected functions. The pleiotropic functions and patterns of expression of K+-channels may provide additional therapeutic opportunities, along with new emerging challenges from off-target effects. Here we review the functions and therapeutic potential of K+-channels, with an emphasis on the nervous system, roles in neuropsychiatric disorders and their involvement in other organ systems and diseases.
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Affiliation(s)
| | - Pernille Svalastoga
- Mohn Center for Diabetes Precision Medicine, Department of Clinical Science, University of Bergen, Bergen, Norway; Children and Youth Clinic, Haukeland University Hospital, Bergen, Norway
| | | | - Jeffrey Colm Glennon
- Conway Institute for Biomolecular and Biomedical Research, School of Medicine, University College Dublin, Dublin, Ireland.
| | - Jan Haavik
- Department of Biomedicine, University of Bergen, Norway; Division of Psychiatry, Haukeland University Hospital, Norway.
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24
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Peng H, Wang M, Wang S, Wang X, Fan M, Qin X, Wu Y, Chen D, Li J, Hu Y, Wu T. KCNQ1 rs2237892 polymorphism modify the association between short-term ambient particulate matter exposure and fasting blood glucose: A family-based study. THE SCIENCE OF THE TOTAL ENVIRONMENT 2023; 876:162820. [PMID: 36921852 DOI: 10.1016/j.scitotenv.2023.162820] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/02/2022] [Revised: 03/08/2023] [Accepted: 03/08/2023] [Indexed: 05/10/2023]
Abstract
BACKGROUND The association between particulate matter and fasting blood glucose (FBG) has shown conflicting results. Genome-wide association studies have shown that KCNQ1 rs2237892 polymorphism is associated with the risk of diabetes. Whether KCNQ1 rs2237892 polymorphism might modify the association between particulate matter and FBG is still uncertain. METHODS Data collected from a family-based cohort study in Northern China, were used to perform the analysis. A generalized additive Gaussian model was used to examine the short-term effects of air pollutants on FBG. We further conducted interaction analyses by including a cross-product term of air pollutants by rs2237892 within KCNQ1 gene. RESULTS A total of 4418 participants were included in the study. In the single pollutant model, the FBG level increased 0.0031 mmol/L with per 10 μg/m3 elevation in fine particular matter (PM2.5) for lag 0 day. After additional adjustments for nitrogen dioxide (NO2) and sulfur dioxide (SO2), similar results were observed for lag 0-2 days. As for particulate matter with particle size below 10 μm (PM10), the significant association between the daily average concentration of the pollutant and FBG level was observed for lag 0-3 days. Additionally, rs2237892 in KCNQ1 gene modified the association between PM and FBG level. The higher risk of FBG levels associated with elevations in PM10 and PM2.5 were more evident as the number of risk allele C increased. Individuals with a CC genotype had the highest risk of elevation in FBG levels. CONCLUSION Short-term exposures to PM2.5 and PM10 were associated with higher FBG levels. Additionally, rs2237892 in KCNQ1 gene might modify the association between the air pollutants and FBG levels.
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Affiliation(s)
- Hexiang Peng
- Department of Epidemiology and Biostatistics, School of Public Health, Peking University, Beijing 100191, China
| | - Mengying Wang
- Department of Epidemiology and Biostatistics, School of Public Health, Peking University, Beijing 100191, China
| | - Siyue Wang
- Department of Epidemiology and Biostatistics, School of Public Health, Peking University, Beijing 100191, China
| | - Xueheng Wang
- Department of Epidemiology and Biostatistics, School of Public Health, Peking University, Beijing 100191, China
| | - Meng Fan
- Department of Epidemiology and Biostatistics, School of Public Health, Peking University, Beijing 100191, China
| | - Xueying Qin
- Department of Epidemiology and Biostatistics, School of Public Health, Peking University, Beijing 100191, China
| | - Yiqun Wu
- Department of Epidemiology and Biostatistics, School of Public Health, Peking University, Beijing 100191, China
| | - Dafang Chen
- Department of Epidemiology and Biostatistics, School of Public Health, Peking University, Beijing 100191, China
| | - Jing Li
- Department of Epidemiology and Biostatistics, School of Public Health, Peking University, Beijing 100191, China
| | - Yonghua Hu
- Department of Epidemiology and Biostatistics, School of Public Health, Peking University, Beijing 100191, China
| | - Tao Wu
- Department of Epidemiology and Biostatistics, School of Public Health, Peking University, Beijing 100191, China.
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Huang C, Guo Y, Li W, Xiang B, Zeng J, Zhou F, She L, Zhang P, Wang S, Liu B, Dai Q, Yang M. Association of the CDKAL1 gene polymorphism with gestational diabetes mellitus in Chinese women. BMJ Open Diabetes Res Care 2023; 11:11/2/e003164. [PMID: 37055162 PMCID: PMC10106001 DOI: 10.1136/bmjdrc-2022-003164] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/09/2022] [Accepted: 03/21/2023] [Indexed: 04/15/2023] Open
Abstract
INTRODUCTION To identify the association of the cyclin-dependent kinase 5 regulatory subunit associated protein 1-like 1 (CDKAL1) gene polymorphism with gestational diabetes mellitus (GDM) in the Chinese population. RESEARCH DESIGN AND METHODS This case-control study enrolled 835 pregnant women with GDM and 870 pregnant women without diabetes who underwent antenatal examination during 24 to 28 gestational weeks at the Maternal and Child Health Hospital of Hubei Province from January 15, 2018 to March 31, 2019. Trained nurses collected their clinical information and blood samples. CDKAL1 gene rs10440833, rs10946398, rs4712523, rs4712524, rs7754840, rs7756992 and rs9465871 loci were genotyped by Agena MassARRAY system. SPSS V.26.0 software and online SHesis were used to analyze the relationship between CDKAL1 gene polymorphism and GDM susceptibility. RESULTS After being adjusted for maternal age, prepregnancy body mass index (BMI), parity and family history of type 2 diabetes mellitus (T2DM), CDKAL1 gene rs10440833 (AA vs TT, OR=1.631, 95% CI 1.192 to 2.232), rs10946398 (CC vs AA, OR=1.400, 95% CI 1.028 to 1.905), rs4712523 (GG vs AA, OR=1.409, 95% CI 1.038 to 1.913), rs4712524 (GG vs AA, OR=1.418, 95% CI 1.043 to 1.929) and rs7754840 (CC vs GG, OR=1.407, 95% CI 1.036 to 1.911) polymorphisms were all associated with the increased risk of GDM. In addition, there was a powerful linkage disequilibrium (LD) among rs10946398, rs4712523, rs4712524 and rs7754840 (D'>0.900, r2>0.900). And there were significant differences in haplotype CGGC (OR=1.207, 95% CI 1.050 to 1.387) and AAAG (OR=0.829, 95% CI 0.721 o 0.952, p=0.008) between the GDM group and the control group. CONCLUSIONS rs10440833, rs10946398, rs4712523, rs4712524 and rs7754840 of CDKAL1 gene are associated with GDM susceptibility in central Chinese population.
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Affiliation(s)
- Chengjing Huang
- Research Center for Health Promotion in Women, Youth and Children, Hubei Province Key Laboratory of Occupational Hazard Identification and Control, School of Public Health, Wuhan University of Science and Technology, Wuhan, Hubei, china
| | - Yan Guo
- School health center, Wuhan Centers for Disease Prevention and Control, Wuhan, Hubei, China
| | - Wei Li
- Department of Pharmacy, Maternal and Child Health Hospital of Hubei Province, Wuhan, Hubei, China
| | - Bing Xiang
- Research Center for Health Promotion in Women, Youth and Children, Hubei Province Key Laboratory of Occupational Hazard Identification and Control, School of Public Health, Wuhan University of Science and Technology, Wuhan, Hubei, china
| | - Jing Zeng
- Research Center for Health Promotion in Women, Youth and Children, Hubei Province Key Laboratory of Occupational Hazard Identification and Control, School of Public Health, Wuhan University of Science and Technology, Wuhan, Hubei, china
| | - Feng Zhou
- Research Center for Health Promotion in Women, Youth and Children, Hubei Province Key Laboratory of Occupational Hazard Identification and Control, School of Public Health, Wuhan University of Science and Technology, Wuhan, Hubei, china
| | - Lu She
- Research Center for Health Promotion in Women, Youth and Children, Hubei Province Key Laboratory of Occupational Hazard Identification and Control, School of Public Health, Wuhan University of Science and Technology, Wuhan, Hubei, china
| | - Pei Zhang
- Research Center for Health Promotion in Women, Youth and Children, Hubei Province Key Laboratory of Occupational Hazard Identification and Control, School of Public Health, Wuhan University of Science and Technology, Wuhan, Hubei, china
| | - Shiwei Wang
- Research Center for Health Promotion in Women, Youth and Children, Hubei Province Key Laboratory of Occupational Hazard Identification and Control, School of Public Health, Wuhan University of Science and Technology, Wuhan, Hubei, china
| | - Bei Liu
- Department of Popular Science, Jinan Health Publicity and Education Center, Jinan, China
| | - Qiong Dai
- Department of Popular Science, Maternal and Child Health Hospital of Hubei Province, Wuhan, Hubei, China
| | - Mei Yang
- Research Center for Health Promotion in Women, Youth and Children, Hubei Province Key Laboratory of Occupational Hazard Identification and Control, School of Public Health, Wuhan University of Science and Technology, Wuhan, Hubei, china
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Sakashita T, Nakamura Y, Sutoh Y, Shimizu A, Hachiya T, Otsuka-Yamasaki Y, Takashima N, Kadota A, Miura K, Kita Y, Ikezaki H, Otonari J, Tanaka K, Shimanoe C, Koyama T, Watanabe I, Suzuki S, Nakagawa-Senda H, Hishida A, Tamura T, Kato Y, Okada R, Kuriki K, Katsuura-Kamano S, Watanabe T, Tanoue S, Koriyama C, Oze I, Koyanagi YN, Nakamura Y, Kusakabe M, Nakatochi M, Momozawa Y, Wakai K, Matsuo K. Comparison of the loci associated with HbA1c and blood glucose levels identified by a genome-wide association study in the Japanese population. Diabetol Int 2023; 14:188-198. [PMID: 37090135 PMCID: PMC10113415 DOI: 10.1007/s13340-023-00618-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/05/2022] [Accepted: 01/15/2023] [Indexed: 01/28/2023]
Abstract
Aims Hemoglobin A1c (HbA1c) levels are widely employed to diagnose diabetes. However, estimates of the heritability of HbA1c and glucose levels are different. Therefore, we explored HbA1c- and blood glucose-associated loci in a non-diabetic Japanese population. Methods We conducted a two-stage genome-wide association study (GWAS) on variants associated with HbA1c and blood glucose levels in a Japanese population. In the initial stage, data of 4911 participants of the Japan Multi-Institutional Collaborative Cohort (J-MICC) were subjected to discovery analysis. In the second stage, two datasets from the Tohoku Medical Megabank project, with 8175 and 40,519 participants, were used for the replication study. Association of the imputed variants with HbA1c and blood glucose levels was determined via linear regression analyses adjusted for age, sex, body mass index (BMI), smoking, and genetic principal components (PC1-PC10). Moreover, we performed a BMI-stratified GWAS on HbA1c levels in the J-MICC. The discovery analysis and BMI-stratified GWAS results were validated with re-analyses of normalized HbA1c levels adjusted for site in addition to the above, and blood glucose adjusted for fasting time as an additional covariate. Results Genetic variants associated with HbA1c levels were identified in KCNQ1 and TMC6. None of the genetic variants associated with blood glucose levels in the discovery analysis were replicated. Association of rs2299620 in KCNQ1 with HbA1c levels showed heterogeneity between individuals with BMI ≥ 25 kg/m2 and BMI < 25 kg/m2. Conclusions The variant rs2299620 in KCNQ1 might affect HbA1c levels differentially based on BMI grouping in the Japanese population. Supplementary Information The online version contains supplementary material available at 10.1007/s13340-023-00618-0.
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Affiliation(s)
- Takuya Sakashita
- Department of Public Health, Shiga University of Medical Science, Seta Tsukinowa-cho, Otsu, Shiga 520-2192 Japan
- TAKARA BIO INC., 7-4-38 Nojihigashi, Kusatsu, Shiga 525-0058 Japan
| | - Yasuyuki Nakamura
- Department of Public Health, Shiga University of Medical Science, Seta Tsukinowa-cho, Otsu, Shiga 520-2192 Japan
- Takeda Hospital Medical Examination Center, Kyoto, Japan
| | - Yoichi Sutoh
- Division of Biomedical Information Analysis, Iwate Tohoku Medical Megabank Organization, Iwate Medical University, 1-1-1 Idaidori, Yahaba-cho, Shiwa-gun, Iwate, 028-3694 Japan
| | - Atsushi Shimizu
- Division of Biomedical Information Analysis, Iwate Tohoku Medical Megabank Organization, Iwate Medical University, 1-1-1 Idaidori, Yahaba-cho, Shiwa-gun, Iwate, 028-3694 Japan
| | - Tsuyoshi Hachiya
- Division of Biomedical Information Analysis, Iwate Tohoku Medical Megabank Organization, Iwate Medical University, 1-1-1 Idaidori, Yahaba-cho, Shiwa-gun, Iwate, 028-3694 Japan
| | - Yayoi Otsuka-Yamasaki
- Division of Biomedical Information Analysis, Iwate Tohoku Medical Megabank Organization, Iwate Medical University, 1-1-1 Idaidori, Yahaba-cho, Shiwa-gun, Iwate, 028-3694 Japan
| | - Naoyuki Takashima
- Department of Public Health, Shiga University of Medical Science, Seta Tsukinowa-cho, Otsu, Shiga 520-2192 Japan
- Department of Public Health, Faculty of Medicine, Kindai University, 377-2 Ohnohigashi, Osaka-Sayama, Osaka 589-8511 Japan
- Department of Epidemiology for Community Health and Medicine, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kamigyo- ku, Kyoto, 602-8566 Japan
| | - Aya Kadota
- Department of Public Health, Shiga University of Medical Science, Seta Tsukinowa-cho, Otsu, Shiga 520-2192 Japan
- NCD Epidemiology Research Center, Shiga University of Medical Science, Seta Tsukinowa-cho, Otsu, Shiga 520-2192 Japan
| | - Katsuyuki Miura
- Department of Public Health, Shiga University of Medical Science, Seta Tsukinowa-cho, Otsu, Shiga 520-2192 Japan
- NCD Epidemiology Research Center, Shiga University of Medical Science, Seta Tsukinowa-cho, Otsu, Shiga 520-2192 Japan
| | - Yoshikuni Kita
- Department of Public Health, Shiga University of Medical Science, Seta Tsukinowa-cho, Otsu, Shiga 520-2192 Japan
- Faculty of Nursing Science, Tsuruga Nursing University, 78-2-1 Kizaki, Tsuruga, Fukui 914-0814 Japan
| | - Hiroaki Ikezaki
- Department of Comprehensive General Internal Medicine, Faculty of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582 Japan
- Department of General Internal Medicine, Kyushu University Hospital, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582 Japan
| | - Jun Otonari
- Department of Psychosomatic Medicine, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582 Japan
| | - Keitaro Tanaka
- Department of Preventive Medicine, Faculty of Medicine, Saga University, 5-1-1 Nabeshima, Saga, 849-8501 Japan
| | - Chisato Shimanoe
- Department of Pharmacy, Saga University Hospital, 5-1-1 Nabeshima, Saga, 849-8501 Japan
| | - Teruhide Koyama
- Department of Epidemiology for Community Health and Medicine, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kamigyo- ku, Kyoto, 602-8566 Japan
| | - Isao Watanabe
- Department of Epidemiology for Community Health and Medicine, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kamigyo- ku, Kyoto, 602-8566 Japan
| | - Sadao Suzuki
- Department of Public Health, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya, 467-8601 Japan
| | - Hiroko Nakagawa-Senda
- Department of Public Health, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya, 467-8601 Japan
| | - Asahi Hishida
- Department of Preventive Medicine, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550 Japan
| | - Takashi Tamura
- Department of Preventive Medicine, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550 Japan
| | - Yasufumi Kato
- Department of Preventive Medicine, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550 Japan
| | - Rieko Okada
- Department of Preventive Medicine, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550 Japan
| | - Kiyonori Kuriki
- Laboratory of Public Health, Division of Nutritional Sciences, School of Food and Nutritional Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka, 422-8526 Japan
| | - Sakurako Katsuura-Kamano
- Department of Preventive Medicine, Tokushima University Graduate School of Biomedical Sciences, 3-18-15 Kuramoto-cho, Tokushima, 770-8503 Japan
| | - Takeshi Watanabe
- Department of Preventive Medicine, Tokushima University Graduate School of Biomedical Sciences, 3-18-15 Kuramoto-cho, Tokushima, 770-8503 Japan
| | - Shiroh Tanoue
- Department of Epidemiology and Preventive Medicine, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima, 890-8544 Japan
| | - Chihaya Koriyama
- Department of Epidemiology and Preventive Medicine, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima, 890-8544 Japan
| | - Isao Oze
- Division of Cancer Epidemiology and Prevention, Aichi Cancer Center Research Institute, 1-1 Kanokoden, Chikusa-ku, Nagoya, 464-8681 Japan
| | - Yuriko N. Koyanagi
- Division of Cancer Information and Control, Aichi Cancer Center Research Institute, 1-1 Kanokoden, Chikusa-ku, Nagoya, 464-8681 Japan
| | - Yohko Nakamura
- Cancer Prevention Center, Chiba Cancer Center Research Institute, 666-2 Nitona-cho, Chuo-ku, Chiba, 260-8717 Japan
| | - Miho Kusakabe
- Cancer Prevention Center, Chiba Cancer Center Research Institute, 666-2 Nitona-cho, Chuo-ku, Chiba, 260-8717 Japan
| | - Masahiro Nakatochi
- Public Health Informatics Unit, Department of Integrated Health Sciences, Nagoya University Graduate School of Medicine, 1-1-20 Daiko-Minami, Higashi-ku, Nagoya, 461-8673 Japan
| | - Yukihide Momozawa
- Laboratory for Genotyping Development, Center for Integrative Medical Sciences, RIKEN, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa 230-0045 Japan
| | - Kenji Wakai
- Department of Preventive Medicine, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550 Japan
| | - Keitaro Matsuo
- Division of Cancer Epidemiology and Prevention, Aichi Cancer Center Research Institute, 1-1 Kanokoden, Chikusa-ku, Nagoya, 464-8681 Japan
- Division of Cancer Epidemiology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550 Japan
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Shojima N, Yamauchi T. Progress in genetics of type 2 diabetes and diabetic complications. J Diabetes Investig 2023; 14:503-515. [PMID: 36639962 PMCID: PMC10034958 DOI: 10.1111/jdi.13970] [Citation(s) in RCA: 28] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/28/2022] [Revised: 12/12/2022] [Accepted: 12/15/2022] [Indexed: 01/15/2023] Open
Abstract
Type 2 diabetes results from a complex interaction between genetic and environmental factors. Precision medicine for type 2 diabetes using genetic data is expected to predict the risk of developing diabetes and complications and to predict the effects of medications and life-style intervention more accurately for individuals. Genome-wide association studies (GWAS) have been conducted in European and Asian populations and new genetic loci have been identified that modulate the risk of developing type 2 diabetes. Novel loci were discovered by GWAS in diabetic complications with increasing sample sizes. Large-scale genome-wide association analysis and polygenic risk scores using biobank information is making it possible to predict the development of type 2 diabetes. In the ADVANCE clinical trial of type 2 diabetes, a multi-polygenic risk score was useful to predict diabetic complications and their response to treatment. Proteomics and metabolomics studies have been conducted and have revealed the associations between type 2 diabetes and inflammatory signals and amino acid synthesis. Using multi-omics analysis, comprehensive molecular mechanisms have been elucidated to guide the development of targeted therapy for type 2 diabetes and diabetic complications.
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Affiliation(s)
- Nobuhiro Shojima
- Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Toshimasa Yamauchi
- Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
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28
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Juárez-Luis J, Canseco-Ocaña M, Cid-Soto MA, Castro-Martínez XH, Martínez-Hernández A, Orozco L, Hernández-Zavala A, Córdova EJ. Single nucleotide variants in microRNA biosynthesis genes in Mexican individuals. Front Genet 2023; 14:1022912. [PMID: 36968598 PMCID: PMC10037310 DOI: 10.3389/fgene.2023.1022912] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2022] [Accepted: 01/02/2023] [Indexed: 03/08/2023] Open
Abstract
Background: MicroRNAs (miRNAs) are important regulators in a variety of biological processes, and their dysregulation is associated with multiple human diseases. Single nucleotide variants (SNVs) in genes involved in the processing of microRNAs may alter miRNA regulation and could present high allele heterogeneity in populations from different ethnic groups. Thus, the aim of this study was to genotype 15 SNVs in eight genes involved in the miRNA processing pathway in Mexican individuals and compare their frequencies across 21 populations from five continental groups.Methods: Genomic DNA was obtained from 399 healthy Mexican individuals. SNVs in AGO2 (rs2293939 and rs4961280), DGCR8 (rs720012), DICER (rs3742330 and rs13078), DROSHA (rs10719 and rs6877842), GEMIN3 (rs197388 and rs197414), GEMIN4 (rs7813, rs2740349, and rs4968104), TNRC6B (rs9611280), and XP05 (rs11077 and rs34324334) were genotyped using TaqMan probes. The minor allele frequency of each SNV was compared to those reported in the 1,000 Genomes database using chi-squared. Sankey plot was created in the SankeyMATIC package to visualize the frequency range of each variant in the different countries analyzed.Results: In Mexican individuals, all 15 SNVs were found in Hardy-Weinberg equilibrium, with frequencies ranging from 0.04 to 0.45. The SNVs rs4961280, rs2740349, rs34324334, and rs720012 in Mexican individuals had the highest minor allele frequencies worldwide, whereas the minor allele frequencies of rs197388, rs10719, rs197414, and rs1107 were among the lowest in Mexican individuals. The variants had high allele heterogeneity among the sub-continental populations, ranging from monomorphic, as was the case for rs9611280 and rs34324334 in African groups, to >0.50, which was the case for variants rs11077 and rs10719 in most of the populations. Importantly, the variants rs197388, rs720012, and rs197414 had FST values > 0.18, indicating a directional selective process. Finally, the SNVs rs13078 and rs10719 significantly correlated with both latitude and longitude.Conclusion: These data indicate the presence of high allelic heterogeneity in the worldwide distribution of the frequency of SNVs located in components of the miRNA processing pathway, which could modify the genetic susceptibility associated with human diseases in populations with different ancestry.
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Affiliation(s)
- Jesús Juárez-Luis
- Section of Research and Postgraduate, Superior School of Medicine, National Institute Polytechnique, Mexico City, Mexico
| | - Moisés Canseco-Ocaña
- Oncogenomics Consortium Laboratory, National Institute of Genomic Medicine, Mexico City, Mexico
| | - Miguel Angel Cid-Soto
- Oncogenomics Consortium Laboratory, National Institute of Genomic Medicine, Mexico City, Mexico
| | - Xochitl H. Castro-Martínez
- Genomics of Psychiatric and Neurogenerative diseases Laboratory, National Institute of Genomic Medicine, Mexico City, Mexico
| | - Angélica Martínez-Hernández
- Immunogenomics and Metabolic diseases Laboratory, National Institute of Genomic Medicine, Mexico City, Mexico
| | - Lorena Orozco
- Immunogenomics and Metabolic diseases Laboratory, National Institute of Genomic Medicine, Mexico City, Mexico
| | - Araceli Hernández-Zavala
- Section of Research and Postgraduate, Superior School of Medicine, National Institute Polytechnique, Mexico City, Mexico
| | - Emilio J. Córdova
- Oncogenomics Consortium Laboratory, National Institute of Genomic Medicine, Mexico City, Mexico
- *Correspondence: Emilio J. Córdova,
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29
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Azarova I, Polonikov A, Klyosova E. Molecular Genetics of Abnormal Redox Homeostasis in Type 2 Diabetes Mellitus. Int J Mol Sci 2023; 24:4738. [PMID: 36902173 PMCID: PMC10003739 DOI: 10.3390/ijms24054738] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2023] [Revised: 02/20/2023] [Accepted: 02/24/2023] [Indexed: 03/05/2023] Open
Abstract
Numerous studies have shown that oxidative stress resulting from an imbalance between the production of free radicals and their neutralization by antioxidant enzymes is one of the major pathological disorders underlying the development and progression of type 2 diabetes (T2D). The present review summarizes the current state of the art advances in understanding the role of abnormal redox homeostasis in the molecular mechanisms of T2D and provides comprehensive information on the characteristics and biological functions of antioxidant and oxidative enzymes, as well as discusses genetic studies conducted so far in order to investigate the contribution of polymorphisms in genes encoding redox state-regulating enzymes to the disease pathogenesis.
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Affiliation(s)
- Iuliia Azarova
- Department of Biological Chemistry, Kursk State Medical University, 3 Karl Marx Street, 305041 Kursk, Russia
- Laboratory of Biochemical Genetics and Metabolomics, Research Institute for Genetic and Molecular Epidemiology, Kursk State Medical University, 18 Yamskaya Street, 305041 Kursk, Russia
| | - Alexey Polonikov
- Laboratory of Statistical Genetics and Bioinformatics, Research Institute for Genetic and Molecular Epidemiology, Kursk State Medical University, 18 Yamskaya Street, 305041 Kursk, Russia
- Department of Biology, Medical Genetics and Ecology, Kursk State Medical University, 3 Karl Marx Street, 305041 Kursk, Russia
| | - Elena Klyosova
- Laboratory of Biochemical Genetics and Metabolomics, Research Institute for Genetic and Molecular Epidemiology, Kursk State Medical University, 18 Yamskaya Street, 305041 Kursk, Russia
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30
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Bouchi R, Kondo T, Ohta Y, Goto A, Tanaka D, Satoh H, Yabe D, Nishimura R, Harada N, Kamiya H, Suzuki R, Yamauchi T. A consensus statement from the Japan Diabetes Society (JDS): a proposed algorithm for pharmacotherapy in people with type 2 diabetes. Diabetol Int 2023; 14:1-14. [PMID: 36636161 PMCID: PMC9829926 DOI: 10.1007/s13340-022-00605-x] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 10/14/2022] [Indexed: 12/24/2022]
Affiliation(s)
- Ryotaro Bouchi
- Diabetes and Metabolism Information Center, Diabetes Research Center, National Center for Global Health and Medicine, Tokyo, Japan
| | - Tatsuya Kondo
- Department of Diabetes, Metabolism and Endocrinology, Kumamoto University Hospital, Kumamoto, Japan
| | - Yasuharu Ohta
- Division of Endocrinology, Metabolism, Hematological Sciences and Therapeutics, Yamaguchi University Graduate School of Medicine, Yamaguchi, Japan
| | - Atsushi Goto
- Department of Health Data Science, Graduate School of Data Science, Yokohama City University, Kanagawa, Japan
| | - Daisuke Tanaka
- Department of Diabetes, Endocrinology and Nutrition, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Hiroaki Satoh
- Department of Diabetes and Endocrinology, Juntendo University Urayasu Hospital, Chiba, Japan
| | - Daisuke Yabe
- Department of Diabetes, Endocrinology and Metabolism and Department of Rheumatology and Clinical Immunology, Gifu University Graduate School of Medicine, Gifu, Japan
| | - Rimei Nishimura
- Division of Diabetes, Metabolism and Endocrinology, Jikei University School of Medicine, Tokyo, Japan
| | - Norio Harada
- Department of Diabetes, Endocrinology and Nutrition, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Hideki Kamiya
- Division of Diabetes, Department of Internal Medicine, Aichi Medical University, Aichi, Japan
| | - Ryo Suzuki
- Department of Diabetes, Metabolism and Endocrinology, Tokyo Medical University, Tokyo, Japan
| | - Toshimasa Yamauchi
- Department of Diabetes and Metabolic Diseases, University of Tokyo Graduate School of Medicine, Tokyo, Japan
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31
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Bouchi R, Kondo T, Ohta Y, Goto A, Tanaka D, Satoh H, Yabe D, Nishimura R, Harada N, Kamiya H, Suzuki R, Yamauchi T. A consensus statement from the Japan Diabetes Society: A proposed algorithm for pharmacotherapy in people with type 2 diabetes. J Diabetes Investig 2022; 14:151-164. [PMID: 36562245 PMCID: PMC9807160 DOI: 10.1111/jdi.13960] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/30/2022] [Revised: 12/01/2022] [Accepted: 12/02/2022] [Indexed: 12/24/2022] Open
Affiliation(s)
- Ryotaro Bouchi
- Diabetes and Metabolism Information Center, Diabetes Research CenterNational Center for Global Health and MedicineTokyoJapan
| | - Tatsuya Kondo
- Department of Diabetes, Metabolism and EndocrinologyKumamoto University HospitalKumamotoJapan
| | - Yasuharu Ohta
- Division of Endocrinology, Metabolism, Hematological Sciences and TherapeuticsYamaguchi University Graduate School of MedicineUbeJapan
| | - Atsushi Goto
- Department of Health Data Science, Graduate School of Data ScienceYokohama City UniversityYokohamaJapan
| | - Daisuke Tanaka
- Department of Diabetes, Endocrinology and Nutrition, Graduate School of MedicineKyoto UniversityKyotoJapan
| | - Hiroaki Satoh
- Department of Diabetes and EndocrinologyJuntendo University Urayasu HospitalUrayasuJapan
| | - Daisuke Yabe
- Department of Diabetes, Endocrinology and Metabolism and Department of Rheumatology and Clinical ImmunologyGifu University Graduate School of MedicineGifuJapan
| | - Rimei Nishimura
- Division of Diabetes, Metabolism and EndocrinologyJikei University School of MedicineTokyoJapan
| | - Norio Harada
- Department of Diabetes, Endocrinology and Nutrition, Graduate School of MedicineKyoto UniversityKyotoJapan
| | - Hideki Kamiya
- Division of Diabetes, Department of Internal MedicineAichi Medical UniversityNagakuteJapan
| | - Ryo Suzuki
- Department of Diabetes, Metabolism and EndocrinologyTokyo Medical UniversityTokyoJapan
| | - Toshimasa Yamauchi
- Department of Diabetes and Metabolic DiseasesUniversity of Tokyo Graduate School of MedicineTokyoJapan
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32
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Jääskeläinen T, Klemetti MM. Genetic Risk Factors and Gene-Lifestyle Interactions in Gestational Diabetes. Nutrients 2022; 14:nu14224799. [PMID: 36432486 PMCID: PMC9694797 DOI: 10.3390/nu14224799] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2022] [Revised: 11/08/2022] [Accepted: 11/10/2022] [Indexed: 11/16/2022] Open
Abstract
Paralleling the increasing trends of maternal obesity, gestational diabetes (GDM) has become a global health challenge with significant public health repercussions. In addition to short-term adverse outcomes, such as hypertensive pregnancy disorders and fetal macrosomia, in the long term, GDM results in excess cardiometabolic morbidity in both the mother and child. Recent data suggest that women with GDM are characterized by notable phenotypic and genotypic heterogeneity and that frequencies of adverse obstetric and perinatal outcomes are different between physiologic GDM subtypes. However, as of yet, GDM treatment protocols do not differentiate between these subtypes. Mapping the genetic architecture of GDM, as well as accurate phenotypic and genotypic definitions of GDM, could potentially help in the individualization of GDM treatment and assessment of long-term prognoses. In this narrative review, we outline recent studies exploring genetic risk factors of GDM and later type 2 diabetes (T2D) in women with prior GDM. Further, we discuss the current evidence on gene-lifestyle interactions in the development of these diseases. In addition, we point out specific research gaps that still need to be addressed to better understand the complex genetic and metabolic crosstalk within the mother-placenta-fetus triad that contributes to hyperglycemia in pregnancy.
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Affiliation(s)
- Tiina Jääskeläinen
- Department of Food and Nutrition, University of Helsinki, P.O. Box 66, 00014 Helsinki, Finland
- Department of Medical and Clinical Genetics, University of Helsinki, P.O. Box 63, 00014 Helsinki, Finland
- Correspondence:
| | - Miira M. Klemetti
- Department of Medical and Clinical Genetics, University of Helsinki, P.O. Box 63, 00014 Helsinki, Finland
- Department of Obstetrics and Gynecology, Helsinki University Hospital, University of Helsinki, P.O. Box 140, 00029 Helsinki, Finland
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33
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Sánchez-Maldonado JM, Collado R, Cabrera-Serrano AJ, Ter Horst R, Gálvez-Montosa F, Robles-Fernández I, Arenas-Rodríguez V, Cano-Gutiérrez B, Bakker O, Bravo-Fernández MI, García-Verdejo FJ, López JAL, Olivares-Ruiz J, López-Nevot MÁ, Fernández-Puerta L, Cózar-Olmo JM, Li Y, Netea MG, Jurado M, Lorente JA, Sánchez-Rovira P, Álvarez-Cubero MJ, Sainz J. Type 2 Diabetes-Related Variants Influence the Risk of Developing Prostate Cancer: A Population-Based Case-Control Study and Meta-Analysis. Cancers (Basel) 2022; 14:cancers14102376. [PMID: 35625981 PMCID: PMC9139180 DOI: 10.3390/cancers14102376] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2022] [Revised: 04/26/2022] [Accepted: 04/29/2022] [Indexed: 02/06/2023] Open
Abstract
In this study, we have evaluated whether 57 genome-wide association studies (GWAS)-identified common variants for type 2 diabetes (T2D) influence the risk of developing prostate cancer (PCa) in a population of 304 Caucasian PCa patients and 686 controls. The association of selected single nucleotide polymorphisms (SNPs) with the risk of PCa was validated through meta-analysis of our data with those from the UKBiobank and FinnGen cohorts, but also previously published genetic studies. We also evaluated whether T2D SNPs associated with PCa risk could influence host immune responses by analysing their correlation with absolute numbers of 91 blood-derived cell populations and circulating levels of 103 immunological proteins and 7 steroid hormones. We also investigated the correlation of the most interesting SNPs with cytokine levels after in vitro stimulation of whole blood, peripheral mononuclear cells (PBMCs), and monocyte-derived macrophages with LPS, PHA, Pam3Cys, and Staphylococcus Aureus. The meta-analysis of our data with those from six large cohorts confirmed that each copy of the FTOrs9939609A, HNF1Brs7501939T, HNF1Brs757210T, HNF1Brs4430796G, and JAZF1rs10486567A alleles significantly decreased risk of developing PCa (p = 3.70 × 10-5, p = 9.39 × 10-54, p = 5.04 × 10-54, p = 1.19 × 10-71, and p = 1.66 × 10-18, respectively). Although it was not statistically significant after correction for multiple testing, we also found that the NOTCH2rs10923931T and RBMS1rs7593730 SNPs associated with the risk of developing PCa (p = 8.49 × 10-4 and 0.004). Interestingly, we found that the protective effect attributed to the HFN1B locus could be mediated by the SULT1A1 protein (p = 0.00030), an arylsulfotransferase that catalyzes the sulfate conjugation of many hormones, neurotransmitters, drugs, and xenobiotic compounds. In addition to these results, eQTL analysis revealed that the HNF1Brs7501939, HNF1Brs757210, HNF1Brs4430796, NOTCH2rs10923931, and RBMS1rs7593730 SNPs influence the risk of PCa through the modulation of mRNA levels of their respective genes in whole blood and/or liver. These results confirm that functional TD2-related variants influence the risk of developing PCa, but also highlight the need of additional experiments to validate our functional results in a tumoral tissue context.
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Affiliation(s)
- José Manuel Sánchez-Maldonado
- Genomic Oncology Area, GENYO, Centre for Genomics and Oncological Research, Pfizer/University of Granada/Andalusian Regional Government, PTS Granada, 18016 Granada, Spain; (J.M.S.-M.); (A.J.C.-S.); (I.R.-F.); (V.A.-R.); (M.J.); (J.A.L.); (M.J.Á.-C.)
- Hematology Department, Virgen de las Nieves University Hospital, 18012 Granada, Spain;
- Instituto de Investigación Biosanataria IBs. Granada, 18012 Granada, Spain
| | - Ricardo Collado
- Medical Oncology Department, Hospital de San Pedro Alcántara, 10003 Cáceres, Spain; (R.C.); (M.I.B.-F.); (J.O.-R.)
| | - Antonio José Cabrera-Serrano
- Genomic Oncology Area, GENYO, Centre for Genomics and Oncological Research, Pfizer/University of Granada/Andalusian Regional Government, PTS Granada, 18016 Granada, Spain; (J.M.S.-M.); (A.J.C.-S.); (I.R.-F.); (V.A.-R.); (M.J.); (J.A.L.); (M.J.Á.-C.)
- Hematology Department, Virgen de las Nieves University Hospital, 18012 Granada, Spain;
- Instituto de Investigación Biosanataria IBs. Granada, 18012 Granada, Spain
| | - Rob Ter Horst
- Department of Internal Medicine and Radboud Centre for Infectious Diseases, Radboud University Nijmegen Medical Center, 6525 GA Nijmegen, The Netherlands; (R.T.H.); (Y.L.); (M.G.N.)
| | - Fernando Gálvez-Montosa
- Department of Medical Oncology, Complejo Hospitalario de Jaén, 23007 Jaén, Spain; (F.G.-M.); (F.J.G.-V.); (J.A.L.L.); (P.S.-R.)
| | - Inmaculada Robles-Fernández
- Genomic Oncology Area, GENYO, Centre for Genomics and Oncological Research, Pfizer/University of Granada/Andalusian Regional Government, PTS Granada, 18016 Granada, Spain; (J.M.S.-M.); (A.J.C.-S.); (I.R.-F.); (V.A.-R.); (M.J.); (J.A.L.); (M.J.Á.-C.)
| | - Verónica Arenas-Rodríguez
- Genomic Oncology Area, GENYO, Centre for Genomics and Oncological Research, Pfizer/University of Granada/Andalusian Regional Government, PTS Granada, 18016 Granada, Spain; (J.M.S.-M.); (A.J.C.-S.); (I.R.-F.); (V.A.-R.); (M.J.); (J.A.L.); (M.J.Á.-C.)
- Department of Biochemistry and Molecular Biology III, Faculty of Medicine, University of Granada, 18016 Granada, Spain;
| | - Blanca Cano-Gutiérrez
- Department of Biochemistry and Molecular Biology III, Faculty of Medicine, University of Granada, 18016 Granada, Spain;
| | - Olivier Bakker
- Department of Genetics, University Medical Center Groningen, University of Groningen, 9713 GZ Groningen, The Netherlands;
| | | | - Francisco José García-Verdejo
- Department of Medical Oncology, Complejo Hospitalario de Jaén, 23007 Jaén, Spain; (F.G.-M.); (F.J.G.-V.); (J.A.L.L.); (P.S.-R.)
| | - José Antonio López López
- Department of Medical Oncology, Complejo Hospitalario de Jaén, 23007 Jaén, Spain; (F.G.-M.); (F.J.G.-V.); (J.A.L.L.); (P.S.-R.)
| | - Jesús Olivares-Ruiz
- Medical Oncology Department, Hospital de San Pedro Alcántara, 10003 Cáceres, Spain; (R.C.); (M.I.B.-F.); (J.O.-R.)
| | | | | | | | - Yang Li
- Department of Internal Medicine and Radboud Centre for Infectious Diseases, Radboud University Nijmegen Medical Center, 6525 GA Nijmegen, The Netherlands; (R.T.H.); (Y.L.); (M.G.N.)
- Centre for Individualised Infection Medicine (CiiM) & TWINCORE, Joint Ventures between the Helmholtz-Centre for Infection Research (HZI) and the Hannover Medical School (MHH), 30625 Hannover, Germany
| | - Mihai G. Netea
- Department of Internal Medicine and Radboud Centre for Infectious Diseases, Radboud University Nijmegen Medical Center, 6525 GA Nijmegen, The Netherlands; (R.T.H.); (Y.L.); (M.G.N.)
- Department for Immunology & Metabolism, Life and Medical Sciences Institute (LIMES), University of Bonn, 53115 Bonn, Germany
| | - Manuel Jurado
- Genomic Oncology Area, GENYO, Centre for Genomics and Oncological Research, Pfizer/University of Granada/Andalusian Regional Government, PTS Granada, 18016 Granada, Spain; (J.M.S.-M.); (A.J.C.-S.); (I.R.-F.); (V.A.-R.); (M.J.); (J.A.L.); (M.J.Á.-C.)
- Hematology Department, Virgen de las Nieves University Hospital, 18012 Granada, Spain;
- Instituto de Investigación Biosanataria IBs. Granada, 18012 Granada, Spain
- Department of Medicine, Faculty of Medicine, University of Granada, 18016 Granada, Spain
| | - Jose Antonio Lorente
- Genomic Oncology Area, GENYO, Centre for Genomics and Oncological Research, Pfizer/University of Granada/Andalusian Regional Government, PTS Granada, 18016 Granada, Spain; (J.M.S.-M.); (A.J.C.-S.); (I.R.-F.); (V.A.-R.); (M.J.); (J.A.L.); (M.J.Á.-C.)
- Department of Legal Medicine, Faculty of Medicine, University of Granada, 18016 Granada, Spain
| | - Pedro Sánchez-Rovira
- Department of Medical Oncology, Complejo Hospitalario de Jaén, 23007 Jaén, Spain; (F.G.-M.); (F.J.G.-V.); (J.A.L.L.); (P.S.-R.)
| | - María Jesús Álvarez-Cubero
- Genomic Oncology Area, GENYO, Centre for Genomics and Oncological Research, Pfizer/University of Granada/Andalusian Regional Government, PTS Granada, 18016 Granada, Spain; (J.M.S.-M.); (A.J.C.-S.); (I.R.-F.); (V.A.-R.); (M.J.); (J.A.L.); (M.J.Á.-C.)
- Department of Biochemistry and Molecular Biology III, Faculty of Medicine, University of Granada, 18016 Granada, Spain;
| | - Juan Sainz
- Genomic Oncology Area, GENYO, Centre for Genomics and Oncological Research, Pfizer/University of Granada/Andalusian Regional Government, PTS Granada, 18016 Granada, Spain; (J.M.S.-M.); (A.J.C.-S.); (I.R.-F.); (V.A.-R.); (M.J.); (J.A.L.); (M.J.Á.-C.)
- Hematology Department, Virgen de las Nieves University Hospital, 18012 Granada, Spain;
- Instituto de Investigación Biosanataria IBs. Granada, 18012 Granada, Spain
- Department of Biochemistry and Molecular Biology I, Faculty of Sciences, University of Granada, 18071 Granada, Spain
- Correspondence: ; Tel.: +34-95871-5500 (ext. 126); Fax: +34-9-5863-7071
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Generation of Isogenic hiPSCs with Targeted Edits at Multiple Intronic SNPs to Study the Effects of the Type 2 Diabetes Associated KCNQ1 Locus in American Indians. Cells 2022; 11:cells11091446. [PMID: 35563754 PMCID: PMC9102014 DOI: 10.3390/cells11091446] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2022] [Revised: 04/11/2022] [Accepted: 04/18/2022] [Indexed: 11/17/2022] Open
Abstract
The top genetic association signal for type 2 diabetes (T2D) in Southwestern American Indians maps to intron 15 of KCNQ1, an imprinted gene. We aim to understand the biology whereby variation at this locus affects T2D specifically in this genomic background. To do so, we obtained human induced pluripotent stem cells (hiPSC) derived from American Indians. Using these iPSCs, we show that imprinting of KCNQ1 and CDKN1C during pancreatic islet-like cell generation from iPSCs is consistent with known imprinting patterns in fetal pancreas and adult islets and therefore is an ideal model system to study this locus. In this report, we detail the use of allele-specific guide RNAs and CRISPR to generate isogenic hiPSCs that differ only at multiple T2D associated intronic SNPs at this locus which can be used to elucidate their functional effects. Characterization of these isogenic hiPSCs identified a few aberrant cell lines; namely cell lines with large hemizygous deletions in the putative functional region of KCNQ1 and cell lines hypomethylated at the KCNQ1OT1 promoter. Comparison of an isogenic cell line with a hemizygous deletion to the parental cell line identified CDKN1C and H19 as differentially expressed during the endocrine progenitor stage of pancreatic-islet development.
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A benzodiazepine activator locks K v7.1 channels open by electro-mechanical uncoupling. Commun Biol 2022; 5:301. [PMID: 35365746 PMCID: PMC8976019 DOI: 10.1038/s42003-022-03229-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2020] [Accepted: 02/22/2022] [Indexed: 01/18/2023] Open
Abstract
Loss-of-function mutations in Kv7.1 often lead to long QT syndrome (LQTS), a cardiac repolarization disorder associated with arrhythmia and subsequent sudden cardiac death. The discovery of agonistic IKs modulators may offer a new potential strategy in pharmacological treatment of this disorder. The benzodiazepine derivative (R)-L3 potently activates Kv7.1 channels and shortens action potential duration, thus may represent a starting point for drug development. However, the molecular mechanisms underlying modulation by (R)-L3 are still unknown. By combining alanine scanning mutagenesis, non-canonical amino acid incorporation, voltage-clamp electrophysiology and fluorometry, and in silico protein modelling, we show that (R)-L3 not only stimulates currents by allosteric modulation of the pore domain but also alters the kinetics independently from the pore domain effects. We identify novel (R)-L3-interacting key residues in the lower S4-segment of Kv7.1 and observed an uncoupling of the outer S4 segment with the inner S5, S6 and selectivity filter segments.
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Associations between KCNQ1 and ITIH4 gene polymorphisms and infant weight gain in early life. Pediatr Res 2022; 91:1290-1295. [PMID: 34247200 DOI: 10.1038/s41390-021-01601-8] [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: 09/24/2020] [Revised: 04/17/2021] [Accepted: 05/20/2021] [Indexed: 11/08/2022]
Abstract
BACKGROUND An earlier meta-analysis of genome-wide association studies in Asian populations detected five novel body mass index-associated single-nucleotide polymorphisms (SNPs), including potassium voltage-gated channel subfamily Q member 1 (KCNQ1) (rs2237892), ALDH2/MYL2 (rs671, rs12229654), ITIH4 (rs2535633), and NT5C2 (rs11191580). Whether these SNPs take effect in early life, for example, affect infant rapid weight gain (RWG), is unclear. METHODS We obtained genomic DNA from 460 term infants with normal birth weight. RWG was defined as the change of weight-for-age standardized Z-score, calculated according to the Children Growth Standard released by the World Health Organization, from birth to 3 months of age >0.67. Using genetic models, associations between the candidate SNPs and infant RWG were examined, along with the interaction between the SNPs and the potential risk factors. RESULTS RWG was presented in 225 of 460 infants. SNP rs2535633 and rs2237892 were associated with the risk of RWG. Both additive and multiplicative interaction effects were found between infant delivery mode and rs2237892. The negative association between the rs2237892 T allele and infant RWG was only observed in vaginally delivered infants. CONCLUSIONS Obesity-related loci rs2535633 and rs2237892 are associated with infant RWG in the first 3 months of infancy. The relationship between rs2237892 and infant RGW might be moderated by cesarean delivery. IMPACT Genetic predisposition is an essential aspect to understand infant weight gain. Obesity-related SNPs, rs2535633 and rs2237892, are associated with RWG in very early years of life. The negative association between rs2237892 T allele and RWG is only observed in infants delivered vaginally instead of cesarean section.
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AmazonForest: In Silico Metaprediction of Pathogenic Variants. BIOLOGY 2022; 11:biology11040538. [PMID: 35453737 PMCID: PMC9024711 DOI: 10.3390/biology11040538] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/26/2022] [Revised: 02/19/2022] [Accepted: 03/02/2022] [Indexed: 11/17/2022]
Abstract
Simple Summary ClinVar is a valuable platform that stores a large set of relevant genetic associations with complex phenotypes. However, the functional impact of a partial set of such associations remains misinterpreted, due to the presence of variants with uncertain significance or with conflicting pathogenicity interpretations. To fill this gap, we present AmazonForest: a metaprediction model based on Random Forest for pathogenicity prediction. AmazonForest was used to reclassify a set of ∼101,000 variants that were predicted as having high pathogenic probability. AmazonForest is available as a web tool with a simple web interface, and also as an R object for pathogenicity predictions. Abstract ClinVar is a web platform that stores ∼789,000 genetic associations with complex diseases. A partial set of these cataloged genetic associations has challenged clinicians and geneticists, often leading to conflicting interpretations or uncertain clinical impact significance. In this study, we addressed the (re)classification of genetic variants by AmazonForest, which is a random-forest-based pathogenicity metaprediction model that works by combining functional impact data from eight prediction tools. We evaluated the performance of representation learning algorithms such as autoencoders to propose a better strategy. All metaprediction models were trained with ClinVar data, and genetic variants were annotated with eight functional impact predictors cataloged with SnpEff/SnpSift. AmazonForest implements the best random forest model with a one hot data-encoding strategy, which shows an Area Under ROC Curve of ≥0.93. AmazonForest was employed for pathogenicity prediction of a set of ∼101,000 genetic variants of uncertain significance or conflict of interpretation. Our findings revealed ∼24,000 variants with high pathogenic probability (RFprob≥0.9). In addition, we show results for Alzheimer’s Disease as a demonstration of its application in clinical interpretation of genetic variants in complex diseases. Lastly, AmazonForest is available as a web tool and R object that can be loaded to perform pathogenicity predictions.
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Lubberding AF, Juhl CR, Skovhøj EZ, Kanters JK, Mandrup‐Poulsen T, Torekov SS. Celebrities in the heart, strangers in the pancreatic beta cell: Voltage-gated potassium channels K v 7.1 and K v 11.1 bridge long QT syndrome with hyperinsulinaemia as well as type 2 diabetes. Acta Physiol (Oxf) 2022; 234:e13781. [PMID: 34990074 PMCID: PMC9286829 DOI: 10.1111/apha.13781] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2021] [Revised: 12/20/2021] [Accepted: 01/02/2022] [Indexed: 12/13/2022]
Abstract
Voltage‐gated potassium (Kv) channels play an important role in the repolarization of a variety of excitable tissues, including in the cardiomyocyte and the pancreatic beta cell. Recently, individuals carrying loss‐of‐function (LoF) mutations in KCNQ1, encoding Kv7.1, and KCNH2 (hERG), encoding Kv11.1, were found to exhibit post‐prandial hyperinsulinaemia and episodes of hypoglycaemia. These LoF mutations also cause the cardiac disorder long QT syndrome (LQTS), which can be aggravated by hypoglycaemia. Interestingly, patients with LQTS also have a higher burden of diabetes compared to the background population, an apparent paradox in relation to the hyperinsulinaemic phenotype, and KCNQ1 has been identified as a type 2 diabetes risk gene. This review article summarizes the involvement of delayed rectifier K+ channels in pancreatic beta cell function, with emphasis on Kv7.1 and Kv11.1, using the cardiomyocyte for context. The functional and clinical consequences of LoF mutations and polymorphisms in these channels on blood glucose homeostasis are explored using evidence from pre‐clinical, clinical and genome‐wide association studies, thereby evaluating the link between LQTS, hyperinsulinaemia and type 2 diabetes.
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Affiliation(s)
- Anniek F. Lubberding
- Department of Biomedical Sciences Faculty of Health and Medical Sciences University of Copenhagen Copenhagen Denmark
| | - Christian R. Juhl
- Department of Biomedical Sciences Faculty of Health and Medical Sciences University of Copenhagen Copenhagen Denmark
| | - Emil Z. Skovhøj
- Department of Biomedical Sciences Faculty of Health and Medical Sciences University of Copenhagen Copenhagen Denmark
| | - Jørgen K. Kanters
- Department of Biomedical Sciences Faculty of Health and Medical Sciences University of Copenhagen Copenhagen Denmark
| | - Thomas Mandrup‐Poulsen
- Department of Biomedical Sciences Faculty of Health and Medical Sciences University of Copenhagen Copenhagen Denmark
| | - Signe S. Torekov
- Department of Biomedical Sciences Faculty of Health and Medical Sciences University of Copenhagen Copenhagen Denmark
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Sanguinetti MC, Seebohm G. Physiological Functions, Biophysical Properties, and Regulation of KCNQ1 (K V7.1) Potassium Channels. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2022; 1349:335-353. [PMID: 35138621 DOI: 10.1007/978-981-16-4254-8_15] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
KCNQ1 (KV7.1) K+ channels are expressed in multiple tissues, including the heart, pancreas, colon, and inner ear. The gene encoding the KCNQ1 protein was discovered by a positional cloning effort to determine the genetic basis of long QT syndrome, an inherited ventricular arrhythmia that can cause sudden death. Mutations in KCNQ1 can also cause other types of arrhythmia (i.e., short QT syndrome, atrial fibrillation) and the gene may also have a role in diabetes and certain cancers. KCNQ1 α-subunits can partner with accessory β-subunits (KCNE1-KCNE5) to form K+-selective channels that have divergent biophysical properties. In the heart, KCNQ1 α-subunits coassemble with KCNE1 β-subunits to form channels that conduct IKs, a very slowly activating delayed rectifier K+ current. KV7.1 channels are highly regulated by PIP2, calmodulin, and phosphorylation, and rich pharmacology includes blockers and gating modulators. Recent biophysical studies and a cryo-EM structure of the KCNQ1-calmodulin complex have provided new insights into KV7.1 channel function, and how interactions between KCNQ1 and KCNE subunits alter the gating properties of heteromultimeric channels.
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Affiliation(s)
| | - Guiscard Seebohm
- Cellular Electrophysiology and Molecular Biology, Institute for Genetics of Heart Diseases, University Hospital Münster, Münster, Germany
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40
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Zeng Q, Zou D, Gu S, Han F, Cao S, Wei Y, Guo R. Different Associations Between CDKAL1 Variants and Type 2 Diabetes Mellitus Susceptibility: A Meta-analysis. Front Genet 2022; 12:783078. [PMID: 35069684 PMCID: PMC8766415 DOI: 10.3389/fgene.2021.783078] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2021] [Accepted: 12/13/2021] [Indexed: 11/13/2022] Open
Abstract
Background: CDK5 regulatory subunit associated protein 1 like 1 (CDKAL1) is a major pathogenesis-related protein for type 2 diabetes mellitus (T2DM). Recently, some studies have investigated the association of CDKAL1 susceptibility variants, including rs4712523, rs4712524, and rs9460546 with T2DM. However, the results were inconsistent. This study aimed to evaluate the association of CDKAL1 variants and T2DM patients. Methods: A comprehensive meta-analysis was performed to assess the association between CDKAL1 SNPs and T2DM among dominant, recessive, additive, and allele models. Results: We investigated these three CDKAL1 variants to identify T2DM risk. Our findings were as follows: rs4712523 was associated with an increased risk of T2DM for the allele model (G vs A: OR = 1.172; 95% CI: 1.103-1.244; p < 0.001) and dominant model (GG + AG vs AA: OR = 1.464; 95% CI: 1.073-1.996; p = 0.016); rs4712524 was significantly associated with an increased risk of T2DM for the allele model (G vs A: OR = 1.146; 95% CI: 1.056-1.245; p = 0.001), additive model (GG vs AA: OR = 1.455; 95% CI: 1.265-1.673; p < 0.001) recessive model (GG vs AA + AG: OR = 1.343; 95% CI: 1.187-1.518; p < 0.001) and dominant model (GG + AG vs AA: OR = 1.221; 95% CI: 1.155-1.292; p < 0.001); and rs9460546 was associated with an increased risk of T2DM for the allele model (G vs T: OR = 1.215; 95% CI: 1.167-1.264; p = 0.023). The same results were found in the East Asian subgroup for the allele model. Conclusions: Our findings suggest that CDKAL1 polymorphisms (rs4712523, rs4712524, and rs9460546) are significantly associated with T2DM.
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Affiliation(s)
- Qiaoli Zeng
- Department of Internal Medicine, Shunde Women and Children's Hospital (Maternity and Child Healthcare Hospital of Shunde Foshan), Guangdong Medical University, Foshan, China.,Key Laboratory of Research in Maternal and Child Medicine and Birth Defects, Guangdong Medical University, Foshan, China.,Matenal and Child Research Institute, Shunde Women and Children's Hospital (Maternity and Child Healthcare Hospital of Shunde Foshan), Guangdong Medical University, Foshan, China
| | - Dehua Zou
- Key Laboratory of Research in Maternal and Child Medicine and Birth Defects, Guangdong Medical University, Foshan, China.,Matenal and Child Research Institute, Shunde Women and Children's Hospital (Maternity and Child Healthcare Hospital of Shunde Foshan), Guangdong Medical University, Foshan, China.,State Key Laboratory for Quality Research of Chinese Medicines, Macau University of Science and Technology, Taipa, Macau SAR, China
| | - Shanshan Gu
- Matenal and Child Research Institute, Shunde Women and Children's Hospital (Maternity and Child Healthcare Hospital of Shunde Foshan), Guangdong Medical University, Foshan, China.,Institute of Neurology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
| | - Fengqiong Han
- Department of Obstetric, Shunde Women and Children's Hospital (Maternity and Child Healthcare Hospital of Shunde Foshan), Guangdong Medical University, Foshan, China
| | - Shilin Cao
- Department of Medical, Shunde Women and Children's Hospital (Maternity and Child Healthcare Hospital of Shunde Foshan), Guangdong Medical University, Foshan, China
| | - Yue Wei
- Department of Ultrasound, Shunde Women and Children's Hospital (Maternity and Child Healthcare Hospital of Shunde Foshan), Guangdong Medical University, Foshan, China
| | - Runmin Guo
- Department of Internal Medicine, Shunde Women and Children's Hospital (Maternity and Child Healthcare Hospital of Shunde Foshan), Guangdong Medical University, Foshan, China.,Key Laboratory of Research in Maternal and Child Medicine and Birth Defects, Guangdong Medical University, Foshan, China.,Matenal and Child Research Institute, Shunde Women and Children's Hospital (Maternity and Child Healthcare Hospital of Shunde Foshan), Guangdong Medical University, Foshan, China.,Department of Endocrinology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
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Xu J, Zhang W, Song W, Cui J, Tian Y, Chen H, Huang P, Yang S, Wang L, He X, Wang L, Shi B, Cui W. Relationship Between KCNQ1 Polymorphism and Type 2 Diabetes Risk in Northwestern China. Pharmgenomics Pers Med 2022; 14:1731-1751. [PMID: 35002291 PMCID: PMC8725845 DOI: 10.2147/pgpm.s340813] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2021] [Accepted: 11/10/2021] [Indexed: 11/23/2022] Open
Abstract
Purpose This study aimed to explore the relationship between KCNQ1 polymorphism and type 2 diabetes mellitus (T2DM) risk in the population of Northwest China. Patients and Methods Case-control strategy was used to reveal the correlation between KCNQ1 polymorphism and T2DM risk, and MDR analysis clarified the influence of KCNQ1 polymorphism interaction on T2DM risk. The related proteins, functions, and signal pathways of KCNQ1 were further explored through bioinformatics methods. PCR was used to explore the relative expression of KCNQ1 in T2DM patients and the controls. Results Studies showed that rs163177, rs163184, rs2237895 and rs2283228 on the KCNQ1 gene are closely related to the risk of T2DM in Northwest China. MDR results showed that the three-locus model is the best model for T2DM risk assessment, which increases the risk of T2DM. The bioinformatics results showed that KCNQ1 closely-acted proteins are mainly involved in signal pathways such as gastric acid secretion and renin secretion. The PCR results showed that, compared with the controls, the expression of KCNQ1 was up-regulated in T2DM patients. Conclusion The results revealed that KCNQ1 polymorphism is related to the risk of T2DM in the population of Northwest China and provide a scientific basis for the early screening and prevention of T2DM high-risk populations.
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Affiliation(s)
- Jing Xu
- Department of Endocrinology and Second Department of Geriatrics, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, People's Republic of China
| | - Wei Zhang
- Department of Breast Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, People's Republic of China
| | - Wei Song
- Department of Endocrinology and Second Department of Geriatrics, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, People's Republic of China
| | - Jiaqi Cui
- Department of Endocrinology and Second Department of Geriatrics, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, People's Republic of China
| | - Yanni Tian
- Department of Endocrinology and Second Department of Geriatrics, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, People's Republic of China
| | - Huan Chen
- Department of Endocrinology and Second Department of Geriatrics, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, People's Republic of China
| | - Pan Huang
- Department of Endocrinology and Second Department of Geriatrics, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, People's Republic of China
| | - Shujun Yang
- Department of Endocrinology and Second Department of Geriatrics, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, People's Republic of China
| | - Lu Wang
- Department of Endocrinology and Second Department of Geriatrics, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, People's Republic of China
| | - Xin He
- Department of Endocrinology, Xi'an Aerospace General Hospital, Xi'an, Shaanxi, 710000, People's Republic of China
| | - Lin Wang
- Department of Endocrinology, Xi'an Gaoxin Hospital, Xi'an, Shaanxi, 710075, People's Republic of China
| | - Bingyin Shi
- Department of Endocrinology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, People's Republic of China
| | - Wei Cui
- Department of Endocrinology and Second Department of Geriatrics, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, People's Republic of China
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Abstract
Since prehistory, human species have depended on plants for both food and medicine. Even in countries with ready access to modern medicines, alternative treatments are still highly regarded and commonly used. Unlike modern pharmaceuticals, many botanical medicines are in widespread use despite a lack of safety and efficacy data derived from controlled clinical trials and often unclear mechanisms of action. Contributing to this are the complex and undefined composition and likely multifactorial mechanisms of action and multiple targets of many botanical medicines. Here, we review the newfound importance of the ubiquitous KCNQ subfamily of voltage-gated potassium channels as targets for botanical medicines, including basil, capers, cilantro, lavender, fennel, chamomile, ginger, and Camellia, Sophora, and Mallotus species. We discuss the implications for the traditional use of these plants for disorders such as seizures, hypertension, and diabetes and the molecular mechanisms of plant secondary metabolite effects on KCNQ channels.
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Affiliation(s)
- Kaitlyn E Redford
- Bioelectricity Laboratory, Department of Physiology and Biophysics, School of Medicine, University of California, Irvine, California 92697, USA;
| | - Geoffrey W Abbott
- Bioelectricity Laboratory, Department of Physiology and Biophysics, School of Medicine, University of California, Irvine, California 92697, USA;
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Bartolomé A. Stem Cell-Derived β Cells: A Versatile Research Platform to Interrogate the Genetic Basis of β Cell Dysfunction. Int J Mol Sci 2022; 23:501. [PMID: 35008927 PMCID: PMC8745644 DOI: 10.3390/ijms23010501] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2021] [Revised: 12/27/2021] [Accepted: 12/29/2021] [Indexed: 02/07/2023] Open
Abstract
Pancreatic β cell dysfunction is a central component of diabetes progression. During the last decades, the genetic basis of several monogenic forms of diabetes has been recognized. Genome-wide association studies (GWAS) have also facilitated the identification of common genetic variants associated with an increased risk of diabetes. These studies highlight the importance of impaired β cell function in all forms of diabetes. However, how most of these risk variants confer disease risk, remains unanswered. Understanding the specific contribution of genetic variants and the precise role of their molecular effectors is the next step toward developing treatments that target β cell dysfunction in the era of personalized medicine. Protocols that allow derivation of β cells from pluripotent stem cells, represent a powerful research tool that allows modeling of human development and versatile experimental designs that can be used to shed some light on diabetes pathophysiology. This article reviews different models to study the genetic basis of β cell dysfunction, focusing on the recent advances made possible by stem cell applications in the field of diabetes research.
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Affiliation(s)
- Alberto Bartolomé
- Instituto de Investigaciones Biomédicas Alberto Sols, CSIC-UAM, 28029 Madrid, Spain
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44
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Asahara SI, Inoue H, Kido Y. Regulation of Pancreatic β-Cell Mass by Gene-Environment Interaction. Diabetes Metab J 2022; 46:38-48. [PMID: 35135077 PMCID: PMC8831821 DOI: 10.4093/dmj.2021.0045] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/15/2021] [Accepted: 05/28/2021] [Indexed: 11/15/2022] Open
Abstract
The main pathogenic mechanism of diabetes consists of an increase in insulin resistance and a decrease in insulin secretion from pancreatic β-cells. The number of diabetic patients has been increasing dramatically worldwide, especially in Asian people whose capacity for insulin secretion is inherently lower than that of other ethnic populations. Causally, changes of environmental factors in addition to intrinsic genetic factors have been considered to have an influence on the increased prevalence of diabetes. Particular focus has been placed on "gene-environment interactions" in the development of a reduced pancreatic β-cell mass, as well as type 1 and type 2 diabetes mellitus. Changes in the intrauterine environment, such as intrauterine growth restriction, contribute to alterations of gene expression in pancreatic β-cells, ultimately resulting in the development of pancreatic β-cell failure and diabetes. As a molecular mechanism underlying the effect of the intrauterine environment, epigenetic modifications have been widely investigated. The association of diabetes susceptibility genes or dietary habits with gene-environment interactions has been reported. In this review, we provide an overview of the role of gene-environment interactions in pancreatic β-cell failure as revealed by previous reports and data from experiments.
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Affiliation(s)
- Shun-ichiro Asahara
- Division of Diabetes and Endocrinology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Hiroyuki Inoue
- Division of Medical Chemistry, Department of Metabolism and Diseases, Kobe University Graduate School of Health Sciences, Kobe, Japan
| | - Yoshiaki Kido
- Division of Diabetes and Endocrinology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Japan
- Division of Medical Chemistry, Department of Metabolism and Diseases, Kobe University Graduate School of Health Sciences, Kobe, Japan
- Corresponding author: Yoshiaki Kido https://orcid.org/0000-0003-2433-5799 Department of Metabolism and Diseases, Kobe University Graduate School of Health Sciences, 7-10-2 Tomogaoka, Suma-ku, Kobe 654-0142, Japan E-mail:
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Synergistic effect between the KCNQ1 haplotype and alcohol consumption on the development of type 2 diabetes mellitus in Korean cohorts. Sci Rep 2021; 11:21796. [PMID: 34750480 PMCID: PMC8575903 DOI: 10.1038/s41598-021-01399-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2021] [Accepted: 10/05/2021] [Indexed: 11/27/2022] Open
Abstract
Potassium voltage-gated channel subfamily Q member 1 (KCNQ1) is one of the strongest susceptibility genes for type 2 diabetes mellitus (T2DM). Association studies between KCNQ1 genetic variants and T2DM have been reported. The multifactorial disease T2DM is caused by interactions between genetic susceptibility and environmental factors. In this study, we examined the associations between the KCNQ1 haplotype, which consists of the major alleles rs3852528, rs11024175, and rs2237892 (ht: ACC), and environmental factors such as alcohol consumption, which are related to the risk of T2DM, in two independent Korean populations. Data from health examination studies, i.e., HEXA (n = 50,357 subjects) and the Ansung–Ansan community-based Korean cohort study (n = 7603), were analyzed. In both cohorts, fasting blood glucose levels were significantly increased in moderate-to-heavy drinkers and carriers of the homozygous ACC haplotype. A significant association between the KCNQ1 haplotype and alcohol consumption in the risk of diabetes was observed in the HEXA (OR 1.587; 95% CI 1.128–2.234) and Ansung–Ansan (OR 2.165; 95% CI 1.175–3.989) cohorts compared with abstainers not carrying the KCNQ1 haplotype. Associations of the KCNQ1 haplotype with alcohol consumption and β-cell function were observed in the Ansung–Ansan cohort. Moderate-to-heavy drinkers with the ACC haplotype had lower fasting insulin levels and mean 60 min insulinogenic index (IGI60) compared with light drinkers and abstainers not carrying the ACC haplotype. These findings indicate that KCNQ1 variants play a synergistic role with alcohol consumption in the development of T2DM and impaired β-cell function.
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The role of long non-coding RNAs in the regulation of pancreatic beta cell identity. Biochem Soc Trans 2021; 49:2153-2161. [PMID: 34581756 PMCID: PMC8589412 DOI: 10.1042/bst20210207] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2021] [Revised: 09/02/2021] [Accepted: 09/08/2021] [Indexed: 12/29/2022]
Abstract
Type 2 diabetes (T2D) is a widespread disease affecting millions in every continental population. Pancreatic β-cells are central to the regulation of circulating glucose, but failure in the maintenance of their mass and/or functional identity leads to T2D. Long non-coding RNAs (lncRNAs) represent a relatively understudied class of transcripts which growing evidence implicates in diabetes pathogenesis. T2D-associated single nucleotide polymorphisms (SNPs) have been identified in lncRNA loci, although these appear to function primarily through regulating β-cell proliferation. In the last decade, over 1100 lncRNAs have been catalogued in islets and the roles of a few have been further investigated, definitively linking them to β-cell function. These studies show that lncRNAs can be developmentally regulated and show highly tissue-specific expression. lncRNAs regulate neighbouring β-cell-specific transcription factor expression, with knockdown or overexpression of lncRNAs impacting a network of other key genes and pathways. Finally, gene expression analysis in studies of diabetic models have uncovered a number of lncRNAs with roles in β-cell function. A deeper understanding of these lncRNA roles in maintaining β-cell identity, and its deterioration, is required to fully appreciate the β-cell molecular network and to advance novel diabetes treatments.
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Bonus M, Häussinger D, Gohlke H. Liver cell hydration and integrin signaling. Biol Chem 2021; 402:1033-1045. [PMID: 33915604 DOI: 10.1515/hsz-2021-0193] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2021] [Accepted: 04/12/2021] [Indexed: 12/21/2022]
Abstract
Liver cell hydration (cell volume) is dynamic and can change within minutes under the influence of hormones, nutrients, and oxidative stress. Such volume changes were identified as a novel and important modulator of cell function. It provides an early example for the interaction between a physical parameter (cell volume) on the one hand and metabolism, transport, and gene expression on the other. Such events involve mechanotransduction (osmosensing) which triggers signaling cascades towards liver function (osmosignaling). This article reviews our own work on this topic with emphasis on the role of β1 integrins as (osmo-)mechanosensors in the liver, but also on their role in bile acid signaling.
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Affiliation(s)
- Michele Bonus
- Institute for Pharmaceutical and Medicinal Chemistry, Heinrich Heine University Düsseldorf, Universitätsstr. 1, D-40225 Düsseldorf, Germany
| | - Dieter Häussinger
- Clinic for Gastroenterology, Hepatology, and Infectious Diseases, Heinrich Heine University Düsseldorf, Moorenstr. 5, D-40225 Düsseldorf, Germany
| | - Holger Gohlke
- Institute for Pharmaceutical and Medicinal Chemistry, Heinrich Heine University Düsseldorf, Universitätsstr. 1, D-40225 Düsseldorf, Germany
- John von Neumann Institute for Computing (NIC), Jülich Supercomputing Centre (JSC), Wilhelm-Johnen-Str., D-52428 Jülich, Germany
- Institute of Biological Information Processing (IBI-7: Structural Biochemistry), and Institute of Bio- and Geosciences (IBG-4: Bioinformatics), Forschungszentrum Jülich GmbH, Wilhelm-Johnen-Str., D-52428 Jülich, Germany
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Multiple Single Nucleotide Polymorphism Testing Improves the Prediction of Diabetic Retinopathy Risk with Type 2 Diabetes Mellitus. J Pers Med 2021; 11:jpm11080689. [PMID: 34442333 PMCID: PMC8398882 DOI: 10.3390/jpm11080689] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2021] [Revised: 07/15/2021] [Accepted: 07/19/2021] [Indexed: 11/17/2022] Open
Abstract
Diabetic retinopathy (DR) is one of the most frequent causes of irreversible blindness, thus prevention and early detection of DR is crucial. The purpose of this study is to identify genetic determinants of DR in individuals with type 2 diabetic mellitus (T2DM). A total of 551 T2DM patients (254 with DR, 297 without DR) were included in this cross-sectional research. Thirteen T2DM-related single nucleotide polymorphisms (SNPs) were utilized for constructing genetic risk prediction model. With logistic regression analysis, genetic variations of the FTO (rs8050136) and PSMD6 (rs831571) polymorphisms were independently associated with a higher risk of DR. The area under the curve (AUC) calculated on known nongenetic risk variables was 0.704. Based on the five SNPs with the highest odds ratio (OR), the combined nongenetic and genetic prediction model improved the AUC to 0.722. The discriminative accuracy of our 5-SNP combined risk prediction model increased in patients who had more severe microalbuminuria (AUC = 0.731) or poor glycemic control (AUC = 0.746). In conclusion, we found a novel association for increased risk of DR at two T2DM-associated genetic loci, FTO (rs8050136) and PSMD6 (rs831571). Our predictive risk model presents new insights in DR development, which may assist in enabling timely intervention in reducing blindness in diabetic patients.
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Jiang HL, Du H, Deng YJ, Liang X. Effect of KCNQ1 rs2237892 polymorphism on the predisposition to type 2 diabetes mellitus: An updated meta-analysis. Diabetol Metab Syndr 2021; 13:75. [PMID: 34238370 PMCID: PMC8264960 DOI: 10.1186/s13098-021-00683-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/10/2021] [Accepted: 06/02/2021] [Indexed: 11/10/2022] Open
Abstract
OBJECTIVES Previous studies have analyzed the potential effect of KCNQ1 rs2237892 polymorphism on the predisposition to type 2 diabetes mellitus, but the findings are inconclusive and the subject of debate. The purpose of our study was to provide further insight into the potential association between KCNQ1 rs2237892 polymorphism and the risk of type 2 diabetes mellitus. METHODS In total, 50 articles (60 studies) with 77,276 cases and 76,054 controls were utilized in our analysis. The pooled odds ratio (OR), 95% confidence interval (95% CI), and p value were used to evaluate the significance of our findings. Funnel plots and Beggar's regression tests were utilized to determine the presence of publication bias. RESULTS Our meta-analysis results indicated that KCNQ1 rs2237892 polymorphism could be correlated with the risk of type 2 diabetes mellitus under the C allelic, recessive, and dominant genetic models (OR = 1.25, 95% 1.19-1.32, p < 0.001; OR = 1.50, 95% CI 1.34-1.68, p < 0.001; OR = 1.26, 95% CI 1.14-1.40, p < 0.001, respectively). Additionally, ethnicity analysis revealed that the source of control, case size, and Hardy-Weinberg Equilibrium status were correlated to the polymorphism in the three genetic models. CONCLUSIONS Our meta-analysis demonstrated significant evidence to support the association between KCNQ1 rs2237892 polymorphism and predisposition to type 2 diabetes mellitus.
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Affiliation(s)
- Hong-Liang Jiang
- Department of Anorectal Medicine, Gaozhou Hospital of Traditional Chinese Medicine, Guangzhou University of Chinese Medicine, Gaozhou, 525025, Guangdong, China
| | - Han Du
- Dermatology Department of Gaozhou Hospital of Traditional Chinese Medicine, Guangzhou University of Chinese Medicine, No. 32 Maoming Avenue, Gaozhou, 525025, Guangdong, China.
| | - Ying-Jun Deng
- The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, 510006, Guangdong, China
| | - Xue Liang
- Department of Science and Education, Gaozhou Hospital of Traditional Chinese Medicine, Guangzhou University of Chinese Medicine, Gaozhou, 525025, Guangdong, China
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Fedotkina O, Sulaieva O, Ozgumus T, Cherviakova L, Khalimon N, Svietleisha T, Buldenko T, Ahlqvist E, Asplund O, Groop L, Nilsson PM, Lyssenko V. Novel Reclassification of Adult Diabetes Is Useful to Distinguish Stages of β-Cell Function Linked to the Risk of Vascular Complications: The DOLCE Study From Northern Ukraine. Front Genet 2021; 12:637945. [PMID: 34276762 PMCID: PMC8283002 DOI: 10.3389/fgene.2021.637945] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2020] [Accepted: 06/03/2021] [Indexed: 12/14/2022] Open
Abstract
Background Presently, persons with diabetes are classified as having type 1 (T1D) or type 2 diabetes (T2D) based on clinical diagnosis. However, adult patients exhibit diverse clinical representations and this makes treatment approaches challenging to personalize. A recent Scandinavian study proposed a novel classification of adult diabetes into five clusters based on disease pathophysiology and risk of vascular complications. The current study aimed to characterize new subgroups of adult diabetes using this strategy in a defined population from northern Ukraine. Methods We analyzed 2,140 patients with established diabetes from the DOLCE study (n = 887 with new-onset diabetes and n = 1,253 with long duration). We used the k-means approach to perform clustering analyses using BMI, age at onset of diabetes, HbA1c, insulin secretion (HOMA2-B), and insulin resistance (HOMA2-IR) indices and glutamic acid decarboxylase antibodies (GADA) levels. Risks of macro- (myocardial infarction or stroke) and microvascular [retinopathy, chronic kidney disease (CKD) and neuropathy] complications and associations of genetic variants with specific clusters were studied using logistic regression adjusted for age, sex, and diabetes duration. Results Severe autoimmune diabetes (SAID, 11 and 6%) and severe insulin-deficient diabetes (SIDD, 25 and 14%) clusters were twice as prevalent in patients with long-term as compared to those with new-onset diabetes. Patients with long duration in both SAID and SIDD clusters had highest risks of proliferative retinopathy, and elevated risks of CKD. Long-term insulin-resistant obese diabetes 1 (IROD1) subgroup had elevated risks of CKD, while insulin-resistant obese diabetes 2 (IROD2) cluster exhibited the highest HOMA2-B, lowest HbA1c, and lower prevalence of all microvascular complications as compared to all other clusters. Genetic analyses of IROD2 subgroup identified reduced frequency of the risk alleles in the TCF7L2 gene as compared to all other clusters, cumulatively and individually (p = 0.0001). Conclusion The novel reclassification algorithm of patients with adult diabetes was reproducible in this population from northern Ukraine. It may be beneficial for the patients in the SIDD subgroup to initiate earlier insulin treatment or other anti-diabetic modalities to preserve β-cell function. Long-term diabetes cases with preserved β-cell function and lower risk for microvascular complications represent an interesting subgroup of patients for further investigations of protective mechanisms.
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Affiliation(s)
- Olena Fedotkina
- Department of Clinical Science, Center for Diabetes Research, University of Bergen, Bergen, Norway
| | - Oksana Sulaieva
- Lund University Diabetes Center, Department of Clinical Sciences, Lund University, Skåne University Hospital, Malmö, Sweden.,Medical Laboratory CSD, Kyiv, Ukraine
| | - Turkuler Ozgumus
- Department of Clinical Science, Center for Diabetes Research, University of Bergen, Bergen, Norway
| | | | | | | | - Tetiana Buldenko
- Department of Health Care of Chernihiv Regional State Administration, Chernihiv, Ukraine
| | - Emma Ahlqvist
- Lund University Diabetes Center, Department of Clinical Sciences, Lund University, Skåne University Hospital, Malmö, Sweden
| | - Olof Asplund
- Lund University Diabetes Center, Department of Clinical Sciences, Lund University, Skåne University Hospital, Malmö, Sweden
| | - Leif Groop
- Lund University Diabetes Center, Department of Clinical Sciences, Lund University, Skåne University Hospital, Malmö, Sweden
| | - Peter M Nilsson
- Lund University Diabetes Center, Department of Clinical Sciences, Lund University, Skåne University Hospital, Malmö, Sweden
| | - Valeriya Lyssenko
- Department of Clinical Science, Center for Diabetes Research, University of Bergen, Bergen, Norway.,Lund University Diabetes Center, Department of Clinical Sciences, Lund University, Skåne University Hospital, Malmö, Sweden
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