title: 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).
abstract: BACKGROUND
  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.
  
  
  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 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).
  
  
  CONCLUSIONS
  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.
authors.affiliation: General Medicine Division, Massachusetts General Hospital, Boston, MA, USA.
authors.forename: Jonna L
authors.initials: JL
authors.lastname: Grimsby
authors.forename: Bianca C
authors.initials: BC
authors.lastname: Porneala
authors.forename: Jason L
authors.initials: JL
authors.lastname: Vassy
authors.forename: Quanhe
authors.initials: Q
authors.lastname: Yang
authors.forename: José C
authors.initials: JC
authors.lastname: Florez
authors.forename: Josée
authors.initials: J
authors.lastname: Dupuis
authors.forename: Tiebin
authors.initials: T
authors.lastname: Liu
authors.forename: Ajay
authors.initials: A
authors.lastname: Yesupriya
authors.forename: Man-Huei
authors.initials: MH
authors.lastname: Chang
authors.forename: Renee M
authors.initials: RM
authors.lastname: Ned
authors.forename: Nicole F
authors.initials: NF
authors.lastname: Dowling
authors.forename: Muin J
authors.initials: MJ
authors.lastname: Khoury
authors.forename: James B
authors.initials: JB
authors.lastname: Meigs
mesh_terms: D000328:Adult; D015415:Biomarkers / Q000097:blood; D044383:Black People / Q000235:genetics; D001786:Blood Glucose / Q000235:genetics; D002648:Child; D003920:Diabetes Mellitus / Q000208:ethnology / Q000235:genetics; D003924:Diabetes Mellitus, Type 2 / Q000097:blood* / Q000208:ethnology / Q000401:mortality*; D005006:Ethnicity / Q000235:genetics; D005260:Female; D005787:Gene Frequency / Q000235:genetics; D056426:Genetic Loci; D006442:Glycated Hemoglobin / Q000032:analysis* / Q000235:genetics*; D006801:Humans; D016014:Linear Models; D015810:Linkage Disequilibrium / Q000235:genetics; D008297:Male; D017058:Mexican Americans / Q000235:genetics; D009749:Nutrition Surveys; D020641:Polymorphism, Single Nucleotide; D044469:Racial Groups / Q000235:genetics*; D014481:United States / Q000453:epidemiology; D044465:White People / Q000235:genetics; D055815:Young Adult; D001741:Black or African American
chemical_list: D015415:Biomarkers; D001786:Blood Glucose; D006442:Glycated Hemoglobin