Genetic Analysis of HNF 4 A Polymorphisms in Caucasian-American Type 2 Diabetes

Hepatocyte nuclear factor 4 (HNF4A), the gene for the maturity-onset diabetes of the young type 1 monogenic form of type 2 diabetes, is within the type 2 diabetes– linked region on chromosome 20q12-q13.1 and, consequently, is a positional candidate gene for type 2 diabetes in the general population. Previous studies have identified only a few rare coding mutations. However, recent studies suggest that single nucleotide polymorphisms (SNPs) located near the P2 ( -cell) promoter of HNF4A are associated with diabetes susceptibility. In this study, we evaluated 23 SNPs spanning 111 kb including the HNF4A gene for association with type 2 diabetes in a collection of Caucasian type 2 diabetic patients with end-stage renal disease (n 300) and control subjects (n 310). None of the individual SNPs were associated with type 2 diabetes in this collection of case subjects (P values ranging from 0.06 to 0.99). However, haplotype analysis identifies significant differences between haplotype frequencies in type 2 diabetic case and control subjects (P 0.013 to P < 0.001), with two uncommon “risk” haplotypes (2.4 and 2.2% of chromosomes) and two uncommon “protective” haplotypes (7.1 and 5.0% of chromosomes) accounting for the evidence of association. Our results suggest that type 2 diabetes linked to 20q12–13 is a heterogeneous disease in which different populations may have different type 2 diabetes susceptibility loci.Diabetes 54: 1185–1190, 2005 Several studies have provided evidence for linkage of type 2 diabetes to the long arm of chromosome 20 in Caucasians (1–5) and Asians (6,7), suggesting that one or more type 2 diabetes susceptibility loci are located on chromosome 20q. Hepatocyte nuclear factor 4 (HNF4A) is a candidate gene within this linked region because mutations in HNF4A have been implicated in the maturity-onset diabetes of the young type 1 subtype of type 2 diabetes, a monogenic form of type 2 diabetes characterized by defective insulin secretion (8). HNF4A is a member of the steroid/thyroid hormone receptor superfamily of transcription factors (9), and it interacts with regulatory elements in promoters and enhancers of genes involved in cholesterol, fatty acid, and glucose metabolism (10). Thirteen exons have been identified in HNF4A, and alternative splicing of these exons results in at least nine isoforms of the gene. The transcription of three of these isoforms is driven by an alternate promoter known as P2, which is located 45.5 kb upstream of the P1 promoter (11,12). Recent studies suggest that although both promoters function in pancreatic -cells (13), it is the P2 promoter that primarily drives transcription in these cells (11,12). In previous studies (14,15), we surveyed the coding region of HNF4A and conserved enhancer-like elements in the distal HNF4A promoter, finding no evidence for significant association to type 2 diabetes in the general population. Recently, several groups have evaluated single nucleotide polymorphisms (SNPs) in the P2 region for association with type 2 diabetes. These reports suggest that four SNPs in a 10.7-kb region encompassing the P2 promoter are significantly associated with type 2 diabetes disease status in subjects from Finnish type 2 diabetic families (16) and Ashkenazi Jewish type 2 diabetic families (17).