Polymorphisms in the Insulin-Degrading Enzyme Gene Are Associated With Type 2 Diabetes in Men From the NHLBI Framingham Heart Study

Abstract

Linkage studies have mapped a susceptibility gene for type 2 diabetes to the long arm of chromosome 10, where we have previously identified a quantitative trait locus that affects fasting blood glucose within the Framingham Heart Study cohort. One candidate gene in this region is the insulin-degrading enzyme (IDE), which, in the GK rat model, has been associated with nonobese type 2 diabetes. Single nucleotide polymorphisms (SNPs) were used to map a haplotype block in the 3′ end of IDE, which revealed association with HbA_1c, fasting plasma glucose (FPG), and mean fasting plasma glucose (mFPG) measured over 20 years. The strongest associations were found in a sample of unrelated men. The lowest trait values were associated with a haplotype (TT, f∼0.32) containing the minor allele of rs2209772 and the major allele of the rs1887922 SNP (FPG P < 0.001, mFPG P < 0.003, HbA_1c P < 0.025). Another haplotype (CC, f∼0.16) was associated with elevated HbA_1c (P < 0.002) and type 2 diabetes (P < 0.001, odds ratio 1.96, 95% CI 1.28–3.00). The evidence presented supports the possibility that IDE is a susceptibility gene for diabetes in populations of European descent.