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 A_1c (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 (<em>P</em> &lt; 5.0 &times; 10^-8). In particular, two African ancestry-specific variants, <em>HBB-</em>rs334 and <em>G6PD</em>-rs1050828, which are causal mutations for sickle cell disease and <em>G6PD</em> deficiency, respectively, had &sim;10 times larger effect sizes on HbA_1c levels (&beta; = -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, <em>HBM</em>-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 <em>HBB-</em>rs334 or <em>G6PD</em>-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%, <em>P</em> &lt; 0.001). After recalibration of the HbA_1c level taking <em>HBB</em>-rs334 and <em>G6PD</em>-rs1050828 into account, the prevalence of hyperglycemia in carriers was similar to noncarriers (31.3% vs. 28.4%, <em>P</em> = 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.