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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 , G 6PC2, 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 (β = 0.012 HbA 1c  increase per risk allele, p = 0.04) and MA (β = 0.021, p = 0.005) but not NHB (β = 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.

bmc medical genetics

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