A role for coding functional variants in HNF4A in type 2 diabetes susceptibility.
A role for coding functional variants in HNF4A in type 2 diabetes susceptibility.
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DOI：
10.1007/s00125-010-1916-4
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发表时间：
2011-01
期刊：
影响因子：
8.2
通讯作者：
McCarthy, M. I.
中科院分区：
文献类型：
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作者：
Jafar-Mohammadi, B.;Groves, C. J.;Gjesing, A. P.;Herrera, B. M.;Winckler, W.;Stringham, H. M.;Morris, A. P.;Lauritzen, T.;Doney, A. S. F.;Morris, A. D.;Weedon, M. N.;Swift, A. J.;Kuusisto, J.;Laakso, M.;Altshuler, D.;Hattersley, A. T.;Collins, F. S.;Boehnke, M.;Hansen, T.;Pedersen, O.;Palmer, C. N. A.;Frayling, T. M.;Gloyn, A. L.;McCarthy, M. I.
Rare mutations in the gene (HNF4A) encoding the transcription factor HNF-4A account for ~5% of cases of maturity-onset diabetes of the young (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 5745 cases and 14756 population controls from the UK and Denmark. We also undertook an expanded association-analysis including 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 14279 cases and 26835 controls. We found no association between V255M and type 2 diabetes in either the initial (p=0.28) or 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 [1.08-1.28]; p=1.5×10−4), which was strengthened in the meta-analysis (OR 1.20 [1.10-1.30]; p=2.1×10−5). 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.
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影响因子：
30.8
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通讯作者：
Altshuler, David
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影响因子：
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作者：
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通讯作者：
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影响因子：
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