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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)

Jonna L Grimsby12, Bianca C Porneala1, Jason L Vassy12, Quanhe Yang3, José C Florez1245, Josée Dupuis67, Tiebin Liu3, Ajay Yesupriya3, Man-Huei Chang3, Renee M Ned3, Nicole F Dowling3, Muin J Khoury3, James B Meigs12* and the MAGIC Investigators8

Author Affiliations

1 General Medicine Division, Massachusetts General Hospital, Boston, MA, USA

2 Harvard Medical School, Boston, MA, USA

3 Office of Public Health Genomics, Centers for Disease Control and Prevention, Atlanta, GA, USA

4 Diabetes Unit and Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA, USA

5 Program in Medical and Population Genetics, Broad Institute, Cambridge, MA, USA

6 Boston University School of Public Health, Boston, MA, USA

7 National Heart, Lung, and Blood Institute's Framingham Heart Study, Framingham, MA, USA

8 Meta-analysis of Glucose and Insulin related traits Consortium, a, a

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BMC Medical Genetics 2012, 13:30  doi:10.1186/1471-2350-13-30

Published: 27 April 2012



Hemoglobin A1c (HbA1c) 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) HbA1c-associated risk allele frequencies (RAFs) for SNPs near SPTA1, HFE, ANK1, HK1, ATP11A, FN3K, TMPRSS6, G6PC2, GCK, MTNR1B; 2) association of SNPs with HbA1c and 3) association of SNPs with mortality.


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.


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 HbA1c in NHW (β = 0.012 HbA1c 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).


At many HbA1c loci in NHANES III there is substantial RAF race-ethnic heterogeneity. The combined impact of common HbA1c-associated variants on HbA1c levels varied by race-ethnicity, but did not influence mortality.