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Am J Hum Genet. 2019 Oct 3;105(4):706-718. doi: 10.1016/j.ajhg.2019.08.010. Epub 2019 Sep 26.

Impact of Rare and Common Genetic Variants on Diabetes Diagnosis by Hemoglobin A1c in Multi-Ancestry Cohorts: The Trans-Omics for Precision Medicine Program.

Author information

1
Department of Biostatistics, Boston University School of Public Health, Boston, MA 02118, USA. Electronic address: chloesar@bu.edu.
2
Division of General Internal Medicine, Massachusetts General Hospital, Boston 02114, MA USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA; Programs in Metabolism and Medical & Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. Electronic address: ASLEONG@partners.org.
3
Department of Genetics, University of North Carolina, Chapel Hill, NC 27514, USA.
4
Department of Biostatistics, Boston University School of Public Health, Boston, MA 02118, USA.
5
Human Genetics Center, Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
6
Institute for Translational Genomics and Population Sciences, LABioMed and Department of Pediatrics at Harbor-UCLA Medical Center, Torrance, CA 90502, USA.
7
Division of Endocrinology, Diabetes and Nutrition, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
8
Department of Epidemiology & Prevention, Wake Forest School of Medicine, Winston-Salem, NC 27101, USA.
9
Department of Biostatistics, University of Washington, Seattle, WA 98195, USA.
10
Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA 98108, USA.
11
Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA 98195, USA.
12
Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
13
University of Alabama at Birmingham, Department of Epidemiology, Birmingham, AL 35294, USA.
14
Department of Epidemiology, UNC Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
15
Division of Hematology, Department of Medicine, Johns Hopkins University, Baltimore, MD 21205, USA.
16
University of Maryland School of Medicine, Baltimore, MD 21201, USA.
17
Division of General Internal Medicine, Massachusetts General Hospital, Boston 02114, MA USA.
18
Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA.
19
Department of Epidemiology, Indiana University Fairbanks School of Public Health, Indianapolis, IN 46202, USA; Department of Medicine and Diabetes Translational Research Center, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
20
Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA 98195, USA; Kaiser Permanente Washington Health Research Institute, Seattle, WA 98101, USA; Departments of Epidemiology and Health Services, University of Washington, Seattle, WA 98195, USA.
21
Department of Human Genetics and South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley School of Medicine, Brownsville, TX 78520, USA.
22
Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA; GeneSTAR Research Program, Department of Medicine, Johns Hopkins University, Baltimore, MD 21205, USA.
23
National Heart, Lung, and Blood Institute and Boston University's Framingham Heart Study, Framingham MA 01702, USA; Population Sciences Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20814, USA.
24
Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA 98108, USA; Department of Epidemiology, University of Washington, Seattle, WA 98195, USA.
25
Division of Endocrinology, Diabetes and Nutrition, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD 21201, USA; Geriatrics Research and Education Clinical Center, Baltimore Veterans Administration Medical Center, Baltimore, MD 21201, USA.
26
Department of Biostatistics, Boston University School of Public Health, Boston, MA 02118, USA; National Heart, Lung, and Blood Institute and Boston University's Framingham Heart Study, Framingham MA 01702, USA.
27
National Heart, Lung, and Blood Institute and Boston University's Framingham Heart Study, Framingham MA 01702, USA; Section of Preventive Medicine and Epidemiology, Evans Department of Medicine, Boston University School of Medicine, Boston, MA 02118, USA; Whitaker Cardiovascular Institute and Cardiology Section, Evans Department of Medicine, Boston University School of Medicine, Boston, MA 02118, USA.
28
Departments of Medicine, Pediatrics, and Population Health Science, University of Mississippi Medical Center, Jackson, MS 39216, USA; The Jackson Heart Study, Jackson, MS 39213, USA.
29
Human Genetics Center, Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, University of Texas Health Science Center at Houston, Houston, TX 77030, USA; Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA.
30
Center for Public Health Genomics, University of Virginia, Charlottesville, VA 22908, USA.
31
Division of General Internal Medicine, Massachusetts General Hospital, Boston 02114, MA USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA; Programs in Metabolism and Medical & Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.

Abstract

Hemoglobin A1c (HbA1c) is widely used to diagnose diabetes and assess glycemic control in individuals 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 and/or FN3KRP in Europeans, and G6PD in African-Americans and Hispanics) and we identified an African-ancestry-specific low-frequency variant (rs1039215 in HBG2 and HBE1, minor allele frequency (MAF) = 0.03). The most associated G6PD variant (rs1050828-T, p.Val98Met, 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 we 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.

KEYWORDS:

The Trans-Omics for Precision Medicine (TOPMed) program; hemoglobin A1c; multi-ancestry sample; whole-genome sequence association analyses

PMID:
31564435
PMCID:
PMC6817529
[Available on 2020-04-03]
DOI:
10.1016/j.ajhg.2019.08.010

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