Evaluation of the association of IGF2BP2 variants with type 2 diabetes in French Caucasians

OBJECTIVE—We performed a comprehensive genetic association study of common variation spanning the IGF2BP2 locus in order to replicate the association of the “confirmed” type 2 diabetes susceptibility variants rs4402960 and rs1470579 in the French Caucasian population and to further characterize the susceptibility variants at this novel locus.RESEARCH DESIGN AND METHODS—We genotyped a total of 21 tagging single nucleotide polymorphisms spanning the IGF2BP2 locus in our type 2 diabetes case-control cohort comprising 3,093 French Caucasian subjects.RESULTS—IGF2BP2 variants rs4402960 and rs1470579 were not associated with type 2 diabetes in the present study (P = 0.632 and P = 0.896, respectively). Meta-analysis of genotype data from over 34,000 subjects demonstrated that our inability to replicate rs4402960/rs1470579 was consistent with the findings from several previous genome-wide association study (GWAS) datasets that were underpowered to detect this modest association signal (odds ratio OR] 1.14). We obtained novel evidence that rs9826022, a borderline rare variant (5% minor allele frequency) in the 3′ downstream region, was associated with type 2 diabetes (P = 0.0002; OR 1.53 95% CI 1.22–1.91]). This result was corroborated by the meta-analysis of 10,542 genotypes from the current study and GWAS datasets using both fixed (P = 9.47 × 10⁻⁶; 1.30 1.16–1.46]) and random effects (P = 0.001; 1.30 1.11–1.52)] calculations.CONCLUSIONS—We were unable to replicate the confirmed rs4402960/rs1470579 susceptibility variants but found novel evidence for a rare variant in the 3′ downstream region of IGF2BP2. Further genetic and functional studies are required to identify the etiological IGF2BP2 variants.The insulin-like growth factor 2 mRNA binding protein 2 (IGF2BP2) gene on chromosome 3q27 is a paralog of IGF2BP1, a known regulator of IGF2 gene expression. Genome-wide association studies (GWASs) carried out by the Finland-U.S. Investigation of NIDDM Genetics (FUSION) (1), the Wellcome Trust Case Control Consortium (WTCCC) (2), and the Diabetes Genetics Initiative (DGI) (3) groups each found modest evidence that single nucleotide polymorphisms (SNPs) in the IGF2BP2 region are associated with type 2 diabetes. The subsequent meta-analysis of primary and replication datasets from these GWASs corroborated these findings and identified two strongly correlated IGF2BP2 variants, rs1470579 and rs4402960, as “confirmed” type 2 diabetes susceptibility variants (1–3). By contrast, the French/Canadian GWAS (4) typed 10 SNPs across the IGF2BP2 locus, including rs1470579, in 1,363 subjects, but found no nominal (P < 0.05) association signals at IGF2BP2. In an attempt to replicate the IGF2BP2 association findings in the French Caucasian population in a larger study and to further characterize the susceptibility variants at this novel locus, we performed an association study of HapMap Phase II tag SNPs spanning the IGF2BP2 locus in 3,093 French Caucasian subjects.