Effect of common polymorphisms in the HNF4? promoter on susceptibility to type 2 diabetes in the French Caucasian population

Abstract

Aims/hypothesis: The gene encoding HNF-4α, 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-4α 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 casecontrol 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 HNF4α 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-4α 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-4α and type 2 diabetes in several ethnic groups.

Monogenic Diabetes in the Young, Pharmacogenetics and Relevance to Multifactorial Forms of Type 2 Diabetes

“…Interestingly, some of the diabetes-associated variants account for most of the evidence of linkage to chromosome 20q13 reported in these two populations. Consistent with these results, genetic variation near the P2 region of HNF4A is associated with T2D in other Danish and UK populations, but not in French or other Caucasian populations (83), which argues for genetic heterogeneity in HNF4A variants susceptibility. The causal variant(s) affecting the expression or function of HNF4␣ are still unknown and could result in a combination of relative insulin deficiency and defective regulation of the hepatic gluconeogenesis.…”

Association of variants in genes involved in pancreatic β-cell development and function with type 2 diabetes in North Indians

“…This observation is consistent with observations in many populations emphasizing the role of variants in HNF4A in the manifestation of T2D (Figure 1). 5,6,[19][20][21][22][23][24][25][26][27][28][29] Meta-analysis revealed that the trend for the elevated OR, as found here in North Indians, is seen in 10 other populations. Notably, rs1884613 has higher effect size in North Indians (OR¼1.35 (95%CI 1.17-1.54)) compared with pooled Scandinavian subjects (OR¼1.14 (95%CI 1.06-1.23)), lesser only to Ashkenazi population (OR¼1.70 (95%CI 1.23-2.38)).…”

Association study of genetic polymorphisms of SLC2A10 gene and type 2 diabetes in the Taiwanese population

“…However, the genetic variation of HNF4A in promoter 2 region is not associated with type 2 diabetes in the French Caucasian population [19]. It is possible that some genes other than HNF4A within the 20q13.12 region contribute to the development of type 2 diabetes.…”