Impact of rare and common genetic variants on diabetes diagnosis by hemoglobin A1c in multi-ancestry cohorts: The Trans-Omics for Precision Medicine Program
Impact of rare and common genetic variants on diabetes diagnosis by hemoglobin A1c in multi-ancestry cohorts: The Trans-Omics for Precision Medicine Program
Abstract Hemoglobin A1c (HbA1c) is widely used to diagnose diabetes and assess glycemic control in patients with diabetes. However, nonglycemic determinants, including genetic variation, may influence how accurately HbA1c reflects underlying glycemia. Analyzing the NHLBI Trans-Omics for Precision Medicine (TOPMed) sequence data in 10,338 individuals from five studies and four ancestries (6,158 Europeans, 3,123 African-Americans, 650 Hispanics and 407 East Asians), we confirmed five regions associated with HbA1c (GCK in Europeans and African-Americans, HK1 in Europeans and Hispanics, FN3K/FN3KRP in Europeans and G6PD in African-Americans and Hispanics) and discovered a new African-ancestry specific low-frequency variant (rs1039215 in HBG2/HBE1, minor allele frequency (MAF)=0.03). The most associated G6PD variant (p.Val98Met, rs1050828-T, MAF=12% in African-Americans, MAF=2% in Hispanics) lowered HbA1c (?0.88% in hemizygous males, ?0.34% in heterozygous females) and explained 23% of HbA1c variance in African-Americans and 4% in Hispanics. Additionally, we identified a rare distinct G6PD coding variant (rs76723693 - p.Leu353Pro, MAF=0.5%; ?0.98% in hemizygous males, ?0.46% in heterozygous females) and detected significant association with HbA1c when aggregating rare missense variants in G6PD. We observed similar magnitude and direction of effects for rs1039215 (HBG2) and rs76723693 (G6PD) in the two largest TOPMed African-American cohorts and replicated the rs76723693 association in the UK Biobank African-ancestry participants. These variants in G6PD and HBG2 were monomorphic in the European and Asian samples. African or Hispanic ancestry individuals carrying G6PD variants may be underdiagnosed for diabetes when screened with HbA1c. Thus, assessment of these variants should be considered for incorporation into precision medicine approaches for diabetes diagnosis.
Rich Stephen S、Vasan Ramachandran S、Correa Adolfo、Morrison Alanna C、Rotter Jerome I、Sarnowski Chlo¨|、Xu Huichun、Zheng Xiuwen、Brody Jennifer A、Goodarzi Mark O、Jain Deepti、Liu Ching-Ti、Porneala Bianca C、Wessel Jennifer、Peralta Juan M、Meigs James B、Johnson Andrew D、Mathias Rasika、Reiner Alexander P、DiCorpo Daniel、Naik Rakhi P、Liu Yongmei、Dupuis Jos¨|e、Hu Yao、Raffield Laura M、Curran Joanne E、Perry James A、Mitchell Braxton D、Cupples L Adrienne、Blangero John、Selvin Elizabeth、de Vries Paul S、Highland Heather M、Hidalgo Bertha A、Wu Peitao、Psaty Bruce M、on behalf of the Trans-Omics for Precision Medicine (TOPMed) Diabetes and TOPMed Hematology and Hemostasis working groups and the NHLBI TOPMed Consortium、Manning Alisa K、Leong Aaron、Kooperberg Charles、Guo Xiuqing、Boerwinkle Eric
Center for Public Health Genomics, University of VirginiaNational Heart Lung and Blood institute and Boston University?ˉs Framingham Heart Study||Section of Preventive Medicine and Epidemiology, Evans Department of Medicine, Boston University School of Medicine||Whitaker Cardiovascular Institute and Cardiology Section, Evans Department of Medicine, Boston University School of MedicineDepartments of Medicine, Pediatrics and Population Health Science, University of Mississippi Medical Center||The Jackson Heart StudyHuman Genetics Center, Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, University of Texas Health Science Center at HoustonInstitute for Translational Genomics and Population Sciences, LABioMed and Department of Pediatrics at Harbor-UCLA Medical CenterDepartment of Biostatistics, Boston University School of Public HealthDivision of Endocrinology, Diabetes and Nutrition, Department of Medicine, University of Maryland School of MedicineDepartment of Biostatistics, University of WashingtonCardiovascular Health Research Unit, Department of Medicine, University of WashingtonDivision of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Cedars-Sinai Medical CenterDepartment of Biostatistics, University of WashingtonDepartment of Biostatistics, Boston University School of Public HealthDivision of General Internal Medicine, Massachusetts General HospitalDepartment of Epidemiology, Indiana University Fairbanks School of Public Health||Department of Medicine and Diabetes Translational Research Center, Indiana University School of MedicineDepartment of Human Genetics and South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley School of MedicineDivision of General Internal Medicine, Massachusetts General Hospital||Department of Medicine, Harvard Medical School||Programs in Metabolism and Medical & Population Genetics, Broad Institute of MIT and HarvardNational Heart Lung and Blood institute and Boston University?ˉs Framingham Heart Study||Population Sciences Branch, National Heart, Lung, and Blood Institute, National Institutes of HealthDepartment of Epidemiology, Johns Hopkins Bloomberg School of Public Health||GeneSTAR Research Program, Department of Medicine, Johns Hopkins UniversityDivision of Public Health Sciences, Fred Hutchinson Cancer Research Center||Department of Epidemiology, University of WashingtonDepartment of Biostatistics, Boston University School of Public HealthDivision of Hematology, Department of Medicine, Johns Hopkins UniversityDepartment of Epidemiology & Prevention, Wake Forest School of MedicineDepartment of Biostatistics, Boston University School of Public Health||National Heart Lung and Blood institute and Boston University?ˉs Framingham Heart StudyDivision of Public Health Sciences, Fred Hutchinson Cancer Research CenterDepartment of Genetics, University of North CarolinaDepartment of Human Genetics and South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley School of MedicineUniversity of Maryland School of MedicineDivision of Endocrinology, Diabetes and Nutrition, Department of Medicine, University of Maryland School of Medicine||Geriatrics Research and Education Clinical Center, Baltimore Veterans Administration Medical CenterDepartment of Biostatistics, Boston University School of Public Health||National Heart Lung and Blood institute and Boston University?ˉs Framingham Heart StudyDepartment of Human Genetics and South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley School of MedicineDepartment of Epidemiology, Johns Hopkins Bloomberg School of Public HealthHuman Genetics Center, Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, University of Texas Health Science Center at HoustonDepartment of Epidemiology, UNC Gillings School of Global Public Health, University of North Carolina at Chapel HillUniversity of Alabama at Birmingham, Department of EpidemiologyDepartment of Biostatistics, Boston University School of Public HealthCardiovascular Health Research Unit, Department of Medicine, University of Washington||Kaiser Permanente Washington Health Research Institute||Departments of Epidemiology and Health Services, University of Washington, SeattleDivision of General Internal Medicine, Massachusetts General Hospital||Department of Medicine, Harvard Medical School||Programs in Metabolism and Medical & Population Genetics, Broad Institute of MIT and HarvardDivision of General Internal Medicine, Massachusetts General Hospital||Department of Medicine, Harvard Medical School||Programs in Metabolism and Medical & Population Genetics, Broad Institute of MIT and HarvardDivision of Public Health Sciences, Fred Hutchinson Cancer Research CenterInstitute for Translational Genomics and Population Sciences, LABioMed and Department of Pediatrics at Harbor-UCLA Medical CenterHuman Genetics Center, Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, University of Texas Health Science Center at Houston||Human Genome Sequencing Center, Baylor College of Medicine
医学研究方法基础医学遗传学
Rich Stephen S,Vasan Ramachandran S,Correa Adolfo,Morrison Alanna C,Rotter Jerome I,Sarnowski Chlo¨|,Xu Huichun,Zheng Xiuwen,Brody Jennifer A,Goodarzi Mark O,Jain Deepti,Liu Ching-Ti,Porneala Bianca C,Wessel Jennifer,Peralta Juan M,Meigs James B,Johnson Andrew D,Mathias Rasika,Reiner Alexander P,DiCorpo Daniel,Naik Rakhi P,Liu Yongmei,Dupuis Jos¨|e,Hu Yao,Raffield Laura M,Curran Joanne E,Perry James A,Mitchell Braxton D,Cupples L Adrienne,Blangero John,Selvin Elizabeth,de Vries Paul S,Highland Heather M,Hidalgo Bertha A,Wu Peitao,Psaty Bruce M,on behalf of the Trans-Omics for Precision Medicine (TOPMed) Diabetes and TOPMed Hematology and Hemostasis working groups and the NHLBI TOPMed Consortium,Manning Alisa K,Leong Aaron,Kooperberg Charles,Guo Xiuqing,Boerwinkle Eric.Impact of rare and common genetic variants on diabetes diagnosis by hemoglobin A1c in multi-ancestry cohorts: The Trans-Omics for Precision Medicine Program[EB/OL].(2025-03-28)[2025-04-26].https://www.biorxiv.org/content/10.1101/643932.点此复制
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