@article{13b8cda5fc70495396c25057ecb303d2,
title = "A genome-wide association study identifies blood disorder-related variants influencing hemoglobin A1c with implications for glycemic status in U.S. hispanics/latinos",
abstract = "OBJECTIVE We aimed to identify hemoglobin A1c (HbA1c)-associated genetic variants and examine their implications for glycemic status evaluated by HbA1c in U.S. Hispanics/ Latinos with diverse genetic ancestries. RESEARCH DESIGN AND METHODS We conducted a genome-wide association study (GWAS) of HbA1c in 9,636 U.S. Hispanics/Latinos without diabetes from the Hispanic Community Health Study/ Study of Latinos, followed by a replication among 4,729 U.S. Hispanics/Latinos from three independent studies. RESULTS Our GWAS and replication analyses showed 10 previously known and novel loci associated with HbA1c at genome-wide significance levels (P < 5.0 × 10-8). In particular, two African ancestry-specific variants, HBB-rs334 and G6PD-rs1050828, which are causal mutations for sickle cell disease and G6PD deficiency, respectively, had ∼10 times larger effect sizes on HbA1c levels (β = 20.31% [23.4 mmol/mol]) and 20.35% [23.8 mmol/mol] per minor allele, respectively) compared with other HbA1c-associated variants (0.03-0.04% [0.3-0.4 mmol/mol] per allele). A novel Amerindian ancestry-specific variant, HBM-rs145546625, was associated with HbA1c and hematologic traits but not with fasting glucose. The prevalence of hyperglycemia (prediabetes and diabetes) defined using fasting glucose or oral glucose tolerance test 2-h glucose was similar between carriers of HBB-rs334 or G6PD-rs1050828 HbA1c-lowering alleles and noncarriers, whereas the prevalence of hyperglycemia defined using HbA1c was significantly lower in carriers than in noncarriers (12.2% vs. 28.4%, P < 0.001). After recalibration of the HbA1c level taking HBB-rs334 and G6PD-rs1050828 into account, the prevalence of hyperglycemia in carriers was similar to noncarriers (31.3% vs. 28.4%, P = 0.28). CONCLUSIONS This study in U.S. Hispanics/Latinos found several ancestry-specific alleles associated with HbA1c through erythrocyte-related rather than glycemic-related pathways. The potential influences of these nonglycemic-related variants need to be considered when the HbA1c test is performed.",
author = "Moon, {Jee Young} and Louie, {Tin L.} and Deepti Jain and Tamar Sofer and Claudia Schurmann and Below, {Jennifer E.} and Lai, {Chao Qiang} and Aviles-Santa, {M. Larissa} and Talavera, {Gregory A.} and Smith, {Caren E.} and Petty, {Lauren E.} and Bottinger, {Erwin P.} and Chen, {Yii Der Ida} and Taylor, {Kent D.} and Daviglus, {Martha L.} and Jianwen Cai and Tao Wang and Tucker, {Katherine L.} and Ordov{\'a}s, {Jos{\'e} M.} and Hanis, {Craig L.} and Loos, {Ruth J.F.} and Neil Schneiderman and Rotter, {Jerome I.} and Kaplan, {Robert C.} and Qibin Qi",
note = "Funding Information: HCHS/SOL was performed as a collaborative study supported by contracts from the National Heart, Lung, and Blood Institute (NHLBI) to the University of North Carolina (N01-HC- 65233), University of Miami (N01-HC-65234), Albert Einstein College of Medicine (N01-HC- 65235), Northwestern University (N01-HC- 65236), and San Diego State University (N01-HC-65237). The following institutes/centers/offices contributed to the HCHS/SOL first funding period through a transfer of funds to the NHLBI: the National Institute on Minority Health and Health Disparities, the National Institute on Deafness and Other Communication Disorders, the National Institute of Dental and Craniofacial Research, the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), the National Institute of Neurological Disorders and Stroke, and the National Institutes of Health Office of Dietary Supplements. The Genetic Analysis Center at the University of Washington was supported by NHLBI contracts (HHSN268201300005C AM03) and National Institute of Dental and Craniofacial Research contracts (HHSN268201300005C MOD03). Genotyping efforts were supported by NHLBI HSN 26220/20054C, National Center for Advancing Translational Sciences Clinical and Translational Science Institute grant UL1-TR-000123, and NIDDK Diabetes Research Center (DRC) grant DK-063491. SCHS was supported in part by Division of Intramural Research, National Institute of Allergy and Infectious Diseases grant AI-085014, NIDDK grants DK-020595, DK-073541, and DK-085501, and NHLBI grant HL-102830 from the National Institutes of Health and funds from the University of Texas Health Science Center at Houston. Genotyping services were provided by the Center for Inherited Disease Research, which is funded through a federal contract from the National Institutes of Health to The Johns Hopkins University, contract number HHSN268200782096C. BRPHS was funded by NHLBI grant P50-HL-105185 and National Institute on Aging grant P01-AG-023394. The Andrea and Charles Bronfman Philanthropies supported the BioMe Biobank program. Q.Q. is supported by NHLBI grants K01-HL-129892, R01- HL-060712, and R01-HL-140976, and by NIDDK grants R01-DK-119268 and R01-DK-120870 Funding Information: Acknowledgments. The authors thank the participants and staffs of HCHS/SOL, SCHS, Boston Puerto Rican Health Study, and BioMe Bio-bank for their important contributions. Funding. HCHS/SOL was performed as a collaborative study supported by contracts from the National Heart, Lung, and Blood Institute (NHLBI) to the University of North Carolina (N01-HC-65233), University of Miami (N01-HC-65234), Albert Einstein College of Medicine (N01-HC-65235), Northwestern University (N01-HC-65236), and San Diego State University (N01-HC-65237). The following institutes/centers/ offices contributed to the HCHS/SOL first funding period through a transfer of funds to the NHLBI: the National Institute on Minority Health and Health Disparities, the National Institute on Deafness and Other Communication Disorders, the National Institute of Dental and Craniofacial Research, the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), the National Institute of Neurological Disorders and Stroke, and the National Institutes of Health Office of Dietary Supplements. The Genetic Analysis Center at the University of Washington was supported by NHLBI contracts (HHSN268201300005C AM03) and National Institute of Dental and Craniofacial Research contracts (HHSN268201300005C MOD03). Gen-otyping efforts were supported by NHLBI HSN 26220/20054C, National Center for Advancing Translational Sciences Clinical and Translational Science Institute grant UL1-TR-000123, and NIDDK Diabetes Research Center (DRC) grant DK-063491. SCHS was supported in part by Division of Intramural Research, National Institute of Allergy and Infectious Diseases grant AI-085014, NIDDK grants DK-020595, DK-073541, and DK-085501, and NHLBI grant HL-102830 from the National Institutes of Health and funds from the University of Texas Health Science Center at Houston. Genotyping services were provided by the Center for Inherited Disease Research, which is funded through a federal contract from the National Institutes of Health to The Johns Hopkins University, contract number HHSN268200782096C. BRPHS was funded by NHLBI grant P50-HL-105185 and National Institute on Aging grant P01-AG-023394. The Andrea and Charles Bronfman Philanthropies supported the BioMe Biobank program. Q.Q. is supported by NHLBI grants K01-HL-129892, R01-HL-060712, and R01-HL-140976, and by NIDDK grants R01-DK-119268 and R01-DK-120870. Publisher Copyright: {\textcopyright} 2019 by the American Diabetes Association.",
year = "2019",
month = sep,
day = "1",
doi = "10.2337/dc19-0168",
language = "English (US)",
volume = "42",
pages = "1784--1791",
journal = "Diabetes Care",
issn = "1935-5548",
publisher = "American Diabetes Association Inc.",
number = "9",
}
