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A role for coding functional variants in HNF4A in type 2 diabetes susceptibility.

ABSTRACT: Rare mutations in the gene HNF4A, encoding the transcription factor hepatocyte nuclear factor 4? (HNF-4A), account for ~5% of cases of MODY and more frequent variants in this gene may be involved in multifactorial forms of diabetes. Two low-frequency, non-synonymous variants in HNF4A (V255M, minor allele frequency [MAF] ~0.1%; T130I, MAF ~3.0%)-known to influence downstream HNF-4A target gene expression-are of interest, but previous type 2 diabetes association reports were inconclusive. We aimed to evaluate the contribution of these variants to type 2 diabetes susceptibility through large-scale association analysis.We genotyped both variants in at least 5,745 cases and 14,756 population controls from the UK and Denmark. We also undertook an expanded association analysis that included previously reported and novel genotype data obtained in Danish, Finnish, Canadian and Swedish samples. A meta-analysis incorporating all published association studies of the T130I variant was subsequently carried out in a maximum sample size of 14,279 cases and 26,835 controls.We found no association between V255M and type 2 diabetes in either the initial (p?=?0.28) or the expanded analysis (p?=?0.44). However, T130I demonstrated a modest association with type 2 diabetes in the UK and Danish samples (additive per allele OR 1.17 [95% CI 1.08-1.28]; p?=?1.5?×?10??), which was strengthened in the meta-analysis (OR 1.20 [95% CI 1.10-1.30]; p?=?2.1?×?10??).Our data are consistent with T130I as a low-frequency variant influencing type 2 diabetes risk, but are not conclusive when judged against stringent standards for genome-wide significance. This study exemplifies the difficulties encountered in association testing of low-frequency variants.

SUBMITTER: Jafar-Mohammadi B

PROVIDER: S-EPMC3119815 | biostudies-literature | 2011 Jan

REPOSITORIES: biostudies-literature

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A role for coding functional variants in HNF4A in type 2 diabetes susceptibility.

Jafar-Mohammadi B B Groves C J CJ Gjesing A P AP Herrera B M BM Winckler W W Stringham H M HM Morris A P AP Lauritzen T T Doney A S F AS Morris A D AD Weedon M N MN Swift A J AJ Kuusisto J J Laakso M M Altshuler D D Hattersley A T AT Collins F S FS Boehnke M M Hansen T T Pedersen O O Palmer C N A CN Frayling T M TM Gloyn A L AL McCarthy M I MI

Diabetologia 20100929 1

<h4>Aims/hypothesis</h4>Rare mutations in the gene HNF4A, encoding the transcription factor hepatocyte nuclear factor 4α (HNF-4A), account for ~5% of cases of MODY and more frequent variants in this gene may be involved in multifactorial forms of diabetes. Two low-frequency, non-synonymous variants in HNF4A (V255M, minor allele frequency [MAF] ~0.1%; T130I, MAF ~3.0%)-known to influence downstream HNF-4A target gene expression-are of interest, but previous type 2 diabetes association reports wer ...[more]

PMID: 20878384

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Project description:BACKGROUND:P-selectin, encoded by SELP, has been implicated as an important molecule in the development of arterial stiffness, consequently leading to vascular complications in T2DM. SELP polymorphisms and increased levels of soluble P-selectin (sP-selectin) have been shown to be associated with several inflammatory diseases. The present work was designed to assess nine putative functional non-coding SELP variants in relation to sP-selectin levels and arterial stiffness in T2DM. METHODS:The genetic distribution of rs3917655, rs3917657, rs3917739, rs2235302, rs3917843 was determined by restriction fragment length polymorphism-polymerase chain reaction (RFLP-PCR). Genotyping of rs3917779 was performed by tetra primer amplification-refractory mutation system (ARMS)- PCR. Three SNPs i.e. rs3917853, rs3917854, rs3917855 were genotyped by Sanger sequencing. Construction of haplotypes was performed using PHASE software. The data thus obtained was analyzed by appropriate statistical tools. RESULTS:Two non-coding variants i.e. rs3917657 and rs3917854 of SELP were found to be associated with 2 and 1.7 -fold risk of disease development respectively. However, one non-coding variant rs2235302 was found to provide protection against disease development. Furthermore, variant allele of rs3917854 in T2DM patients was found to be associated with 2.07-fold very high vascular risk. Non-coding haplotype GCAGGCCGC was conferring 4.14-fold risk of disease development. Furthermore, overall sP-selectin levels were higher in T2DM patients when segregated according to genotypes as well as haplotypes. Significant genotype- phenotype correlation was observed for rs3917655 as well as rs3917739 variant in patients and for rs3917854 in controls. In vascular risk categories, a significant genotype- phenotype correlation was observed for rs3917655 and rs2235302. Furthermore, patients with CCGGGCCGC haplotype in high risk category were observed with higher levels of sP-selectin as compared to other haplotypes (p?<?0.05). CONCLUSIONS:Non-coding SELP variants may significantly modulate sP-selectin levels, vascular risk and T2DM susceptibility.

Dataset Information

A role for coding functional variants in HNF4A in type 2 diabetes susceptibility.

Publications

A role for coding functional variants in HNF4A in type 2 diabetes susceptibility.

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