Genetic Analysis of HNF4A Polymorphisms in Caucasian-American Type 2 Diabetes

Abstract

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 diabeteslinked 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 S everal 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 ϳ45.5 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. T...

Hepatocyte Nuclear Factor-4α P2 Promoter Haplotypes Are Associated With Type 2 Diabetes in the Japanese Population

“…However, our result was consistent with that reported in two recent articles published by Bagwell et al (20) and Winckler et al (21), who reported no evidence of any association of single SNPs with type 2 diabetes in Scandinavians and American Caucasians. These discrepant results among the studies may be attributable to the different genetic backgrounds of the subjects.…”

“…Ϫ27 kb upstream of the P2 promoter, and rs6073418, 17kb downstream of the P2 promoter, represents one block of strong LD, which is consistent with previous reports (15,16,20). No difference in the distributions of either the genotypes or the SNPs in HNF4A were observed between the nondiabetic and type 2 diabetic subjects (Table 1).…”

Association of variants in genes involved in pancreatic β-cell development and function with type 2 diabetes in North Indians

“…This observation is consistent with observations in many populations emphasizing the role of variants in HNF4A in the manifestation of T2D (Figure 1). 5,6,[19][20][21][22][23][24][25][26][27][28][29] Meta-analysis revealed that the trend for the elevated OR, as found here in North Indians, is seen in 10 other populations. Notably, rs1884613 has higher effect size in North Indians (OR¼1.35 (95%CI 1.17-1.54)) compared with pooled Scandinavian subjects (OR¼1.14 (95%CI 1.06-1.23)), lesser only to Ashkenazi population (OR¼1.70 (95%CI 1.23-2.38)).…”

P2 Promoter Variants of the Hepatocyte Nuclear Factor 4α Gene Are Associated With Type 2 Diabetes in Mexican Americans

“…The haplotype bearing all "protective" alleles (Hap 3 in Table 3) was present at a frequency of 7.8% and was not associated. Two previous studies (7,10) have identified rare haplotypes within the disequilibrium block encompassing the P2 promoter region, which are significantly associated with type 2 diabetes, although the individual SNPs themselves were not associated. In each study, the associated haplotypes involve rare recombination events between SNP rs2144908 and either rs1884614 or rs1884613.…”