We could show that 12 (57%) (HHEX, HNF1B, IGF2BP2, IRS1, KCNJ11, KCNQ1, NOTCH2, PPARG, TCF7L2, THADA, TSPAN8 and WFS1) out of 21 genes located in vicinity of these SNPs were showing aberrant expression in T2DM from the gene expression profiling studies.
We examined the effect of interactions between seven incretin-related genetic variants in GIPR, KCNQ1, TCF7L2 and WFS1 and dietary components (whey-containing dairy, cereal fibre, coffee and olive oil) on the risk of type 2 diabetes in the European Prospective Investigation into Cancer and Nutrition (EPIC)-InterAct study.
At six loci with genome-wide evidence for T2D association (AP3S2, KCNK16, NOTCH2, SCL30A8, VPS26A, and WFS1) predicted mRNA target sites for islet-expressed miRNAs overlapped potentially causal variants.
Rare mutations in WFS1 cause Wolfram syndrome; using a gene-centric approach, we show that variation in WFS1 also predisposes to common type 2 diabetes.
In addition, we found evidence for association of SNPs in the genes PPARG, IGF2BP2, HHEX, TCF7L2, and FTO with type 2 diabetes in the same directions as previously described (p<0.05), but not for WFS1, CDKN2A/B, KCNJ11, or EXT2.
All the risk alleles in the 11 examined type 2 diabetes risk variants showed an odds ratio (OR) greater than 1 for the GDM group compared with the control group ranging from 1.13 [95% confidence interval (CI) 0.88-1.46] to 1.44 (95% CI 1.19-1.74) except for the WFS1rs10010131 variant with OR 0.87 (95% CI 0.73-1.05).
As common WFS1 gene variants have recently been shown to confer a risk of type 2 diabetes, our findings may be relevant to the gradual but progressive loss of beta cells in type 2 diabetes.
While FTO rs8050136 and rs17817449, ADAMTS9 rs4607103, and WFS1rs10010131 were initially associated with T2DM, this was lost upon multiple testing correction.
Rare mutations in WFS1 cause Wolfram syndrome; using a gene-centric approach, we show that variation in WFS1 also predisposes to common type 2 diabetes.
Not only did an association between WFS1-rs6446482 and early-onset T2D exist in the subgroup analysis, but TCF2-rs7501939 and WFS1-rs6446482 were also confirmed to confer risk for T2D in this meta-analysis.
The most frequent haplotype at the haplotype block containing the WFS1 gene modulated insulin secretion and was associated with an increased risk of type 2 diabetes.