Mutations of WFS1 gene cause Wolfram syndrome, which is a rare autosomalrecessive disorder characterized by juvenile diabetes mellitus, optic atrophy, deafnessand diabetes insipidus. The product encoded by WFS1 gene, wolframin, could beinvolved in ER stress response causing β-cell loss through impaired cell cycleprogression and increased apoptosis. Recently, polymorphisms in the WFS1 gene werestrongly associated with type 2 diabetes in Caucasians. The aim of the present studywas to examine whether the variants of WFS1 are associated with risk of type 2diabetes in Japanese individuals. Four single nucleotide polymorphisms, rs6446482,rs12511742, rs1801208 (R456H) and rs734312 (H611R) were genotyped in a total of 536diabetic patients and 398 nondiabetic control subjects. Among the four variants,rs12511742 showed a marginal association with susceptibility to type 2 diabetes (oddsratio = 1.32, 95% confidence interval = 1.02-1.71, P = 0.033). Carriers of the risk alleleat rs12511742 exhibited lower pancreas β-cell function (P = 0.017). However, thisassociation disappeared after adjustment for sex, age and BMI (Adjusted P = 0.24).Although we found no evidence for a substantial effect of WFS1 polymorphisms on riskof type 2 diabetes or clinical characteristics of diabetic subjects in Japanese population,this gene is still a good candidate for a type 2 diabetes susceptibility gene, potentially,through impaired insulin secretion