1. A Genome-Wide Association Study Identifies Blood Disorder–Related Variants Influencing Hemoglobin A1c With Implications for Glycemic Status in U.S. Hispanics/Latinos
- Author
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Robert C. Kaplan, Katherine L. Tucker, Caren E. Smith, Jose M. Ordovas, Ruth J. F. Loos, Tao Wang, Yii-Der Ida Chen, Tin Louie, Jerome I. Rotter, Jee-Young Moon, Lauren E. Petty, Chao-Qiang Lai, Claudia Schurmann, M. Larissa Avilés-Santa, Tamar Sofer, Kent D. Taylor, Martha L. Daviglus, Neil Schneiderman, Craig L. Hanis, Jennifer E. Below, Jianwen Cai, Gregory A. Talavera, Deepti Jain, Erwin P. Bottinger, and Qibin Qi
- Subjects
Advanced and Specialized Nursing ,Research design ,endocrine system diseases ,business.industry ,Endocrinology, Diabetes and Metabolism ,nutritional and metabolic diseases ,030209 endocrinology & metabolism ,Genome-wide association study ,medicine.disease ,03 medical and health sciences ,0302 clinical medicine ,Blood Disorder ,Diabetes mellitus ,Community health ,Internal Medicine ,Medicine ,030212 general & internal medicine ,Hemoglobin ,Allele ,business ,Glycemic ,Demography - 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 = −0.31% [−3.4 mmol/mol]) and −0.35% [−3.8 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.
- Published
- 2019