Journal
DIABETOLOGIA
Volume 54, Issue 1, Pages 111-119Publisher
SPRINGER
DOI: 10.1007/s00125-010-1916-4
Keywords
HNF4A; Low-frequency variants; T130I; Type 2 diabetes; V255M
Categories
Funding
- Medical Research Council (MRC) [G0000934, 81696]
- Wellcome Trust [068545/Z/02, GR072960]
- Oxford NIHR Biomedical Research Centre
- Danish Agency for Science Technology and Innovation [271-06-0539]
- National Health Services in the counties of Copenhagen, Aarhus, Ringkobing, Ribe and South Jutland
- Danish Research Foundation for General Practice, Danish Centre for Evaluation and Health Technology Assessment
- National Board of Health
- Danish Medical Research Council
- Aarhus University Research Foundation
- Novo Nordisk Foundation
- Novo Nordisk
- Novo Nordisk Scandinavia
- Astra Denmark
- Pfizer Denmark
- GlaxoSmithKline Pharma Denmark
- Servier Denmark
- HemoCue Denmark
- US National Institutes of Health [DK062370, DK072193, HL084729, HG002651, U54 DA021519]
- National Human Genome Research Institute [1 Z01 HG000024]
- Academy of Finland
- EVO [5263]
- Sigrid Juselius Foundation
- Finnish Diabetes Research Foundation
- Folkhalsan Research Foundation
- EC [BM4-CT95-0662]
- Swedish Medical Research Council
- JDF Wallenberg Foundation
- Diabetes UK
- Medical Research Council [G0700222, G0000934] Funding Source: researchfish
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [U01HL084729] Funding Source: NIH RePORTER
- NATIONAL HUMAN GENOME RESEARCH INSTITUTE [R01HG002651, ZIAHG000024] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [R01DK062370, R56DK062370, U01DK062370, R01DK072193] Funding Source: NIH RePORTER
- MRC [G0000934, G0700222] Funding Source: UKRI
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Aims/hypothesis Rare mutations in the gene HNF4A, encoding the transcription factor hepatocyte nuclear factor 4 alpha (HNF-4A), account for similar to 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] similar to 0.1%; T130I, MAF similar to 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 x 10(-4)), which was strengthened in the meta-analysis (OR 1.20 [95% CI 1.10-1.30]; p = 2.1 x 10(-5)). Conclusions 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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