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 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 ( 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 = -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 < 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.
(© 2019 by the American Diabetes Association.)