Race-ethnic differences in the association of genetic loci with HbA1c levels and mortality in US adults: the third National Health and Nutrition Examination Survey (NHANES III)

Background: Hemoglobin A(1c) (HbA(1c)) levels diagnose diabetes, predict mortality and are associated with ten single nucleotide polymorphisms (SNPs) in white individuals. Genetic associations in other race groups are not known. We tested the hypotheses that there is race-ethnic variation in 1) HbA(1c)-associated risk allele frequencies (RAFs) for SNPs near SPTA1, HFE, ANK1, HK1, ATP11A, FN3K, TMPRSS6, G6PC2, GCK, MTNR1B; 2) association of SNPs with HbA(1c) and 3) association of SNPs with mortality. Methods: We studied 3,041 non-diabetic individuals in the NHANES (National Health and Nutrition Examination Survey) III. We stratified the analysis by race/ethnicity (NHW: non-Hispanic white; NHB: non-Hispanic black; MA: Mexican American) to calculate RAF, calculated a genotype score by adding risk SNPs, and tested associations with SNPs and the genotype score using an additive genetic model, with type 1 error = 0.05. Results: RAFs varied widely and at six loci race-ethnic differences in RAF were significant (p < 0.0002), with NHB usually the most divergent. For instance, at ATP11A, the SNP RAF was 54% in NHB, 18% in MA and 14% in NHW (p < .0001). The mean genotype score differed by race-ethnicity (NHW: 10.4, NHB: 11.0, MA: 10.7, p < .0001), and was associated with increase in HbA(1c) in NHW (beta = 0.012 HbA(1c) increase per risk allele, p = 0.04) and MA (beta = 0.021, p = 0.005) but not NHB (beta = 0.007, p = 0.39). The genotype score was not associated with mortality in any group (NHW: OR (per risk allele increase in mortality) = 1.07, p = 0.09; NHB: OR = 1.04, p = 0.39; MA: OR = 1.03, p = 0.71). Conclusion: At many HbA(1c) loci in NHANES III there is substantial RAF race-ethnic heterogeneity. The combined impact of common HbA(1c)-associated variants on HbA(1c) levels varied by race-ethnicity, but did not influence mortality.