We estimated the linkage disequilibrium (LD) pattern assessed by r
2 of the three WFS1 SNPs (rs10010131, rs6446482 and rs734312) (Electronic supplementary material [ESM] Fig. 3). As the LD between rs10010131 and rs6446482 was high (r
2 > 0.95), only rs734312 and rs10010131 were analysed in the present paper. The minor allele frequency in the population-based Inter99 cohort was 42% for rs10010131 and 48% for rs734312.
In the present Danish case–control study, the WFS1 rs734312 showed a borderline significant association with type 2 diabetes with a direction and a relative risk consistent with previous reports (Table 1).
In order to investigate whether intermediate prediabetic phenotypes are associated with the reported WFS1 type 2 diabetes risk alleles, we investigated metabolic traits related to type 2 diabetes in 4,568 glucose-tolerant individuals and in 1,471 treatment-naive individuals with abnormal glucose regulation (IFG, IGT and screen-detected type 2 diabetes). In individuals with abnormal glucose regulation, the diabetogenic risk A allele of rs734312 was associated in an allele-dependent manner with a decreased insulinogenic index (p = 0.025) and a decreased 30-min serum insulin level (p = 0.047) after an oral glucose load, whereas in glucose-tolerant individuals the same allele was associated with increased fasting serum insulin (p = 0.019), fasting serum C-peptide (p = 0.030) and HOMA-IR (p = 0.026; Table 2). Similar results were found for the diabetes risk allele of rs10010131 (ESM Table 1).
We searched results of available web-based genome-wide association studies of WFS1 SNPs and their potential relationships to traits associated with type 2 diabetes such as fasting serum insulin, 120 min post-OGTT serum insulin and insulinogenic index, as well as estimates of insulin resistance. However, no significant associations with any of the ten SNPs genotyped in WFS1 were observed .
We also examined for interaction between glucose tolerance status and genotype by applying a linear model for quantitative indices of pancreatic beta cell function. In this analysis, we demonstrated a significant interaction of rs734312 with traits related to beta cell function (30-min serum insulin p = 0.0088, insulinogenic index p = 0.0025), which implies a larger effect size of WFS1 variants for individuals with abnormal glucose regulation than for glucose tolerant individuals (Table 2, ESM Table 1). In glucose-tolerant people, the effect size on beta cell-related traits such as the insulinogenic index seems to be vague, i.e. 2.2% (95% CI [−4.7, 0.2] reduction per allele, p = 0.075), whereas in the group of individuals with abnormal glucose regulation the impact increases considerably, i.e. 6.5% (95% CI [0.8, 12.1] increase per allele, p = 0.025). Similar results were observed for 30 min serum insulin and C-peptide after an oral glucose load (ESM Table 2).
The interplay between WFS1 rs734312 genotype, insulin release and insulin resistance in relation to glucose tolerance status in the Inter99 cohort is shown in Fig. 1. It appears that there is a glucose tolerance interaction affecting the two correlated traits (p = 0.0017) and that the largest effect is on insulin release as assessed by the insulinogenic index in A allele carriers with abnormal glucose regulation. With regard to rs10010131, an interaction of glucose tolerance status on the insulinogenic index and HOMA-IR was also found to be statistically significant (p = 0.0027, data not shown).