Aim: Mutations in the IPF1 gene cause MODY4; IPF1 D76N is a polymorphism, which inhibits the insulin promoter and decreases insulin-secretion. We planned to estimate the odds ratio (OR) between D76N genotype and type 2 diabetes (T2D) in Italian, European and worldwide cohorts.
Methods: We recruited 90 unrelated late-onset T2D subjects and 50 unrelated control subjects from Italy. We screened the subjects for IPF1 mutations. We sequenced the control subjects' DNA to determine D76N presence/absence and tested for association in the Italian dataset. We estimated the OR for a T2D cohort of D76N carriers by performing a meta-analysis of published data from multiple populations. We performed the association by pooling ORs and we tested for heterogeneity between the different population samples. We analyzed separately total, late-onset and early-onset T2D subjects using both European and worldwide data. The statistical power for each data set was defined.
Results: In the Italian cohort, we identified one late-onset T2D subject and his affected sibling as D76N carriers and one late-onset T2D subject as a carrier of a silent mutation (P244P). Our meta-analysis shows only a trend toward association in the early-onset European population. Given the observed rarity of the putative susceptibility genotype, power to detect a significant association between D76N and T2D for OR < 1.59 was less than 0.8 in all samples.
Conclusion: So far, this is the largest association study regarding the effect of D76N IPF1 on T2D. We conclude that D76N IPF1 is not contributing to T2D in early-onset or late-onset cohorts in the currently present worldwide dataset.