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Jafar-Mohammadi, B.* ; Groves, C.J.* ; Gjesing, A.P.* ; Herrera, BM.* ; Winckler, W.* ; Stringham, H.M.* ; Morris, A.P.* ; Lauritzen, T.* ; Doney, A.S.* ; Morris, A.D.* ; Weedon, M.N.* ; Swift, AJ.* ; Kuusisto, J.* ; Laakso, M.* ; Altshuler, D.* ; Hattersley, A.T.* ; Collins, F.S.* ; Boehnke, M.* ; Hansen, T.* ; Pedersen, O.* ; Palmer, C.N.* ; Frayling, T.M.* ; DIAGRAM Consortium (Huth, C. ; Grallert, H. ; Gieger, C. ; Klopp, N. ; Meitinger, T. ; Petersen, A.-K. ; Thorand, B. ; Wichmann, H.-E. ; Illig, T.) ; Gloyn, AL.* ; McCarthy, M.I.*

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

Diabetologia 54, 111-119 (2011)
DOI PMC
Open Access Green möglich sobald Postprint bei der ZB eingereicht worden ist.
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 were inconclusive. We aimed to evaluate the contribution of these variants to type 2 diabetes susceptibility through large-scale association analysis. METHODS: 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. RESULTS: 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 × 10⁻⁴), which was strengthened in the meta-analysis (OR 1.20 [95% CI 1.10-1.30]; p = 2.1 × 10⁻⁵). CONCLUSIONS/INTERPRETATION: 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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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter HNF4A; Low-frequency variants; T130I; Type 2 diabetes; V255M
Sprache englisch
Veröffentlichungsjahr 2011
HGF-Berichtsjahr 2011
ISSN (print) / ISBN 0012-186X
e-ISSN 1432-0428
Zeitschrift Diabetologia
Quellenangaben Band: 54, Heft: 1, Seiten: 111-119 Artikelnummer: , Supplement: ,
Verlag Springer
Verlagsort Berlin ; Heidelberg [u.a.]
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Genetic Epidemiology (IGE)
Research Unit Molecular Epidemiology (AME)
POF Topic(s) 30501 - Systemic Analysis of Genetic and Environmental Factors that Impact Health
Forschungsfeld(er) Genetics and Epidemiology
PSP-Element(e) G-504100-001
G-504200-002
PubMed ID 20878384
DOI 10.1007/s00125-010-1916-4
Erfassungsdatum 2011-06-29
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