Aims/hypothesis
The gene encoding HNF-4
, an orphan nuclear receptor playing critical roles in embryogenesis and metabolism by regulating gene expression in pancreatic beta cells, liver, and other tissues, is localised to chromosome 20q13, where linkage to type 2 diabetes has been shown in multiple studies. As two reports have independently demonstrated a convincing association with variants adjacent to the
HNF-4 P2 promoter in Finnish and Ashkenazi Jewish populations, we evaluated their contribution to diabetes risk in the French Caucasian population.
Methods
Genotypes for four haplotype tag SNPs were analysed for association with diabetes in a case-control study of 744 unrelated type 2 diabetic patients and 686 normoglycaemic subjects, and for linkage in 148 diabetic families in whom significant linkage to the
HNF4 region had been shown.
Results
The association seen in the Finnish and Ashkenazi studies for SNPs rs2144908 and rs1884614 located within a haplotype block encompassing the beta cell promoter P2 of
HNF-4 was not replicated in our study; in French Caucasians the minor allele prevalence was increased in control subjects [odds ratio (OR) 0.80, uncorrected
p=0.022 for rs2144908; OR 0.82 uncorrected
p=0.058 for rs1884614]. Furthermore, none of the SNPs tested in the French familial sample was associated with diabetes, nor do they appear to contribute to the linkage.
Conclusions/interpretation
None of the previously associated SNPs confer an increased risk for diabetes in French Caucasians. A large meta-analysis of association studies will determine whether there is a consistent association between particular SNPs upstream of
HNF-4 and type 2 diabetes in several ethnic groups.
Keywords Association study - Genetics - Haplotype - HNF-4 - Insulin secretion - SNP - Type 2 diabetes