Analysis of the HNF4α gene in Caucasian Type II diabetic nephropathic patients

Price, Jennifer A.; Fossey, Sallyanne C.; Sale, Michèle M.; Brewer, Catherine; Freedman, Barry I.; Wuerth, Jean-Paul; Bowden, Donald W.

doi:10.1007/s001250050055

Cited by 37 publications

(36 citation statements)

References 42 publications

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“…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.…”

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confidence: 85%

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

et al. 2005

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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...

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confidence: 85%

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

et al. 2005

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“…P2-driven transcripts have been described as the predominant splice variant in pancreatic ␤-cells (18 -21). Although HNF4␣ intragenic and/or proximal P1 promoter single nucleotide polymorphisms (SNPs) have been described in previous type 2 diabetes studies (4,(22)(23)(24)(25)(26), a thorough examination of the P2 region has not been reported; thus, association mapping was designed to examine the P2 region in this study.…”

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confidence: 99%

A Common Polymorphism in the Upstream Promoter Region of the Hepatocyte Nuclear Factor-4α Gene on Chromosome 20q Is Associated With Type 2 Diabetes and Appears to Contribute to the Evidence for Linkage in an Ashkenazi Jewish Population

et al. 2004

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Variants in hepatocyte nuclear factor-4␣ (HNF4␣), a transcription factor that influences the expression of glucose metabolic genes, have been correlated with maturityonset diabetes of the young, a monogenic form of diabetes. Previously, in a genome scan of Ashkenazi Jewish type 2 diabetic families, we observed linkage to the chromosome 20q region encompassing HNF4␣. Here, haplotype-tag single nucleotide polymorphisms (htSNPs) were identified across a 78-kb region around HNF4␣ and evaluated in an association analysis of Ashkenazi Jewish type 2 diabetic (n ‫؍‬ 275) and control (n ‫؍‬ 342) subjects. We found that two of nine htSNPs were associated with type 2 diabetes: a 3 intronic SNP, rs3818247 (29.2% case subjects vs. 21.7% control subjects; P ‫؍‬ 0.0028, odds ratio [OR] 1.49) and a 5 htSNP located ϳ3.9 kb upstream of P2, rs1884614 (26.9% case subjects vs. 20.3% control subjects; P ‫؍‬ 0.0078, OR 1.45). Testing of additional SNPs 5 of rs1884614 revealed a >10-kb haplotype block that was associated with type 2 diabetes. Conditioning on the probands' rs1884614 genotype suggested that the chromosomal region identified by the htSNP accounted for the linkage signal on chromosome 20q in families in which the proband carried at least one risk allele. Notably, the associations and the partitioned linkage profiles near P2 were independently observed in a Finnish sample, suggesting the presence of potential regulatory element(s) that may contribute to the risk for type 2 diabetes.

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“…Mutation analyses of both the P1 and P2 promoters and the coding exons of HNF4A have not identified any SNPs that were associated with type 2 diabetes [17][18][19][20] (own unpublished data). If the observed association with type 2 diabetes is caused by an SNP influencing the expression or function of HNF-4α, it is more likely to be an SNP in a distinct regulatory region of the P2 promoter.…”

Section: Discussionmentioning

confidence: 99%

“…Results from several linkage studies among Caucasians have, however, indicated that variation in the HNF4A region on chromosome 20q12-q13 may also confer an increased risk of type 2 diabetes [10][11][12][13][14][15][16][17]. Previous mutation analyses of the P1, P2 and the coding exons of HNF4A have failed to identify frequent variants which were associated with type 2 diabetes [11,[17][18][19][20]. Recently, however, two independent studies have made important progress in explaining the observed linkage on 20q12-q13.…”

Section: Introductionmentioning

confidence: 99%

Variation near the hepatocyte nuclear factor (HNF)-4? gene associates with type 2 diabetes in the Danish population

et al. 2005

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Aims/hypothesis: The hepatocyte nuclear factor (HNF)-4α is an orphan nuclear receptor, which plays crucial roles in regulating hepatic gluconeogenesis and insulin secretion. The gene encoding HNF-4α (HNF4A) is located on chromosome 20q12-q13 in a region that in several studies has shown linkage with type 2 diabetes. Recently, two independent studies identified single nucleotide polymorphisms (SNPs) in a 90-kb region spanning HNF4A, which showed strong association with type 2 diabetes in the Finnish and Ashkenazi Jewish populations. In an attempt to replicate and extend these findings, we selected four SNPs in the same HNF4A region, which in the Finnish and Ashkenazi Jewish populations were associated with type 2 diabetes, and examined their relationships with type 2 diabetes and prediabetic phenotypes in the Danish Caucasian population. Methods: The rs1884614, rs2425637, rs1885088 and rs3818247 were analysed in case-control studies of 1387, 1429, 1417 and 1371 type 2 diabetic patients and 4766, 4727, 4665 and 4748 glucose-tolerant subjects respectively. Genotype-quantitative trait analyses comprised 4430, 4394, 4336 and 4413 middle-aged glucose-tolerant subjects from the population-based Inter99 cohort for the rs1884614, rs2425637, rs1885088 and rs3818247 respectively. Results: The risk allele of the rs1884614, which is located 4 kb upstream of the HNF4A P2 promoter, was associated with type 2 diabetes (odds ratio [OR]=1.14, p=0.02) and with a subtle increase in post-OGTT plasma glucose levels in glucose-tolerant subjects (additive model, p=0.05). Conclusions/ interpretation: Consistent with results from studies of Finnish and Ashkenazi Jewish subjects, variation near the P2 region of HNF4A is associated with type 2 diabetes in the Danish population.

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Analysis of the HNF4α gene in Caucasian Type II diabetic nephropathic patients

Cited by 37 publications

References 42 publications

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

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

A Common Polymorphism in the Upstream Promoter Region of the Hepatocyte Nuclear Factor-4α Gene on Chromosome 20q Is Associated With Type 2 Diabetes and Appears to Contribute to the Evidence for Linkage in an Ashkenazi Jewish Population

Variation near the hepatocyte nuclear factor (HNF)-4? gene associates with type 2 diabetes in the Danish population

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