Aims/hypothesis: Mutations at the Wolframin encoding gene, WFS1, cause Wolfram
syndrome, a rare neurological condition. Associations between single nucleotide polymorphisms
(SNPs) at WFS1 and type 2 diabetes have recently been reported. In the present study, we sought
to replicate those associations in a northern Swedish case-control study for type 2 diabetes. We
also meta-analyzed published and previously unpublished data from Sweden, Finland and France
to obtain updated summary effect estimates.
Methods: Four WFS1 SNPs (rs10010131, rs6446482, rs752854, rs734312 [R611H]) were
genotyped in a type 2 diabetes case-control study (N=1,296/1,412) of Swedish adults. Logistic
regression was used to assess the association between each WFS1 SNP and type 2 diabetes,
following adjustment for age, sex, and body mass index. We then performed a meta-analysis of 11
studies of type 2 diabetes, comprising up to 14,139 cases and 16,109 controls, to obtain a
summary effect estimate for the WFS1 variants.
Results: In the northern Swedish study, the minor allele at rs752854 was associated with reduced
type 2 diabetes risk (OR=0.85; 95% CI=0.75-0.96; p=0.010). Borderline statistical associations
were observed for the remaining SNPs. The meta-analysis of the four independent replication
studies for SNP rs10010131, or its proxy variants, showed evidence for statistical association
(OR=0.87; 95% CI=0.82-0.93; p=4.5×10−5). In an updated meta-analysis of all 11 studies,
comprising 14,139 cases and 16,109 controls, strong evidence for statistical association was also
observed (OR=0.89; 95% CI=0.86-0.92; p=4.9×10−11). Conclusion: In this study of WFS1 gene variants and type 2 diabetes risk, we have replicated
the previously reported associations between SNPs at this locus and risk of type 2 diabetes
