The effect of WNT5B IVS3C > G on the susceptibility to type 2 diabetes in UK Caucasian subjects

Background and aims: The wnt signaling pathway regulates adipogenesis and insulin secretion. The WNT5B gene has been reported to confer susceptibility to type 2 diabetes (T2D) in the Japanese population, and we therefore evaluated this in Caucasian subjects with respect to obesity status. Methods and results: Two thousand seven hundred and one Caucasian middle-aged men from the prospective Northwick Park Heart Study II (NPHSII) of whom 153 developed T2D over 15 years and 1268 Caucasian middle-aged patients with T2D (60% male) were genotyped using a TaqMan assay for the IVS3C > G variant (rs2270031) in the WNT5B gene. The frequency of the G allele was 0.026 (0.022-0.031) in controls and 0.031 (0.025-0.039) in patients with diabetes, p = 0.24. In the prospective analysis, G allele carriers with BMI below 26 kg/m(2) had significantly higher T2D hazard risk [3.46 (1.34-8.96), p = 0.01]. Comparing T2D cases with NPHSII controls, the G allele was associated with a significantly higher T2D odds ratio (OR) of 1.50 (1.06-2.12), p = 0.02 in subjects with BMI lower than 30 kg/m(2). Increasing BMI had a smaller effect on risk in G allele carriers. The effect on risk was not explained by genotype being associated with any classical. T2D risk factor. When the combined effect of this SNP and the TCF7L2 IVS3C > T SNP (rs7903146) was evaluated, 2.07 (1.40-3.07), p < 0.0001 fold higher OR was observed in carriers of both the rare alleles. Conclusion: Variation in WNT5B predisposes to T2D in the absence of obesity. The increase in risk conferred by the presence of both WNT5B and TCF7L2 variants strengthens the role of wnt signaling in T2D. (C) 2008 Elsevier B.V. All rights reserved.