Disorder-specific effects of polymorphisms at opposing ends of the Insulin Degrading Enzyme gene

BACKGROUND: Insulin-degrading enzyme (IDE) is the ubiquitously expressed enzyme responsible for insulin and amyloid beta (Aβ) degradation. IDE gene is located on chromosome region 10q23-q25 and exhibits a well-replicated peak of linkage with Type 2 diabetes mellitus (T2DM). Several genetic association studies examined IDE gene as a susceptibility gene for Alzheimer's disease (AD), however with controversial results. METHODS: We examined associations of three IDE polymorphisms (IDE2, rs4646953; IDE7, rs2251101 and IDE9, rs1887922) with AD, Aβ(42 )plasma level and T2DM risk in the longitudinal Vienna Transdanube Aging (VITA) study cohort. RESULTS: The upstream polymorphism IDE2 was found to influence AD risk and to trigger the Aβ(42 )plasma level, whereas the downstream polymorphism IDE7 modified the T2DM risk; no associations were found for the intronic variant IDE9. CONCLUSIONS: Based on our SNP and haplotype results, we delineate the model that IDE promoter and 3' untranslated region/downstream variation may have different effects on IDE expression, presumably a relevant endophenotype with disorder-specific effects on AD and T2DM susceptibility.