| Literature DB >> 31564435 |
Chloé Sarnowski1, Aaron Leong2, Laura M Raffield3, Peitao Wu4, Paul S de Vries5, Daniel DiCorpo4, Xiuqing Guo6, Huichun Xu7, Yongmei Liu8, Xiuwen Zheng9, Yao Hu10, Jennifer A Brody11, Mark O Goodarzi12, Bertha A Hidalgo13, Heather M Highland14, Deepti Jain9, Ching-Ti Liu4, Rakhi P Naik15, Jeffrey R O'Connell16, James A Perry16, Bianca C Porneala17, Elizabeth Selvin18, Jennifer Wessel19, Bruce M Psaty20, Joanne E Curran21, Juan M Peralta21, John Blangero21, Charles Kooperberg10, Rasika Mathias22, Andrew D Johnson23, Alexander P Reiner24, Braxton D Mitchell25, L Adrienne Cupples26, Ramachandran S Vasan27, Adolfo Correa28, Alanna C Morrison5, Eric Boerwinkle29, Jerome I Rotter6, Stephen S Rich30, Alisa K Manning31, Josée Dupuis26, James B Meigs31.
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.Entities:
Keywords: The Trans-Omics for Precision Medicine (TOPMed) program; hemoglobin A1c; multi-ancestry sample; whole-genome sequence association analyses
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Year: 2019 PMID： 31564435 PMCID： PMC6817529 DOI： 10.1016/j.ajhg.2019.08.010
Source DB: PubMed Journal: Am J Hum Genet ISSN： 0002-9297 Impact factor: 11.025