A Genome-Wide Association Study Identifies Blood Disorder–Related Variants Influencing Hemoglobin A1c With Implications for Glycemic Status in U.S. Hispanics/Latinos

OBJECTIVE We aimed to identify hemoglobin A1c (HbA 1c )-associated genetic variants and examine their implications for glycemic status evaluated by HbA 1c in U.S. Hispanics/Latinos with diverse genetic ancestries. RESEARCH DESIGN AND METHODS We conducted a genome-wide association study (GWAS) of HbA 1c 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 HbA 1c at genome-wide significance levels ( P −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 HbA 1c levels (β = −0.31% [−3.4 mmol/mol]) and −0.35% [−3.8 mmol/mol] per minor allele, respectively) compared with other HbA 1c -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 HbA 1c 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 HbA 1c -lowering alleles and noncarriers, whereas the prevalence of hyperglycemia defined using HbA 1c was significantly lower in carriers than in noncarriers (12.2% vs. 28.4%, P 1c 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 HbA 1c through erythrocyte-related rather than glycemic-related pathways. The potential influences of these nonglycemic-related variants need to be considered when the HbA 1c test is performed.