Variants in hepatocyte nuclear factor 4alpha are modestly associated with type 2 diabetes in Pima Indians

Abstract

Single nucleotide polymorphisms (SNPs) within the hepatocyte nuclear factor 4alpha (HNF4alpha) gene are associated with type 2 diabetes in Finns and Ashkenazi Jews. Previous studies in both populations have reported linkage to type 2 diabetes near the HNF4alpha locus on chromosome 20q12-13. To investigate whether HNF4alpha is a diabetes susceptibility gene in Pima Indians, a population with the highest reported prevalence of type 2 diabetes but with no evidence for linkage of the disease on chromosome 20q, 19 SNPs across the promoter and coding region of HNF4alpha were genotyped for association analysis. In a group of 1,037 Pima Indians (573 diabetic and 464 nondiabetic subjects), three SNPs in HNF4alpha (rs3212183 and rs2071197 located in introns 3 and 1, respectively, and rs6031558, an extremely rare SNP located in the P2 promoter region) were modestly associated with type 2 diabetes (rs3212183 odds ratio [OR] 1.34 [95% CI 1.07-1.67], P = 0.009; rs2071197 1.34 [1.07-1.66], P = 0.008; and rs6031558 3.18 [1.03-9.84], P = 0.04, adjusted for age, sex, birth year, heritage, and family membership). We conclude that variants in HNF4alpha do not appear to be major determinants for type 2 diabetes in Pima Indians; however, HNF4alpha may have a minor role in type 2 diabetes susceptibility within this Native American population.

FIG. 1

Relative positions of 21 SNPs within the HNF4α locus selected for analysis in Pima Indians. ○, SNPs analyzed for type 2 diabetes in Pima Indians and either Finns or Ashkenazi Jews (or both); □, SNPs analyzed for type 2 diabetes in Pima Indians only; •, SNP (rs3212183) associated with type 2 diabetes in both Pima Indians and Finns; ▪, SNPs (rs2071197 and rs6031558) associated with type 2 diabetes in Pima Indians not typed in other populations. rs2144908* is in complete genotypic concordance with rs1884614; rs6031552* is in complete genotypic concordance with rs6031558.

FIG. 2

Pairwise linkage disequilibrium among SNPs in the HNF4α region in Pima Indians. Values in the upper right represent D′, while values in the bottom left represent Δ². Genotypes of 19 SNPs from 1,037 individuals typed for the diabetes association analysis were used to determine the pairwise linkage disequilibrium.