A genome-wide association study identifies blood disorder-related variants influencing hemoglobin A_1c 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 < 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 HbA_1c levels (β = 20.31% [23.4 mmol/mol]) and 20.35% [23.8 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 < 0.001). After recalibration of the HbA_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.