Abstract for presentation at 11th International Congress of Human Genetics

IDE Variants Associated with Elevated mRNA Reduce Risk for Late-Onset Alzheimer’s Disease

  • Steven Younkin, Mayo Clinic College of Medicine, United States
  • Dr Minerva Carrasquillo, Mayo Clinic College of Medicine, United States
  • Dr Fanggeng Zou, United States
  • Samuel Younkin, Mayo Clinic College of Medicine, United States
  • Dr Linda Younkin, Mayo Clinic College of Medicine, United States
  • Dr Nilufer Taner, Mayo Clinic College of Medicine, United States
  • Dr Ronald Petersen, Mayo Clinic College of Medicine, United States
  • Dr Neill Graff-Radford, Mayo Clinic College of Medicine, United States

    • Purpose: The insulin-degrading-enzyme gene (IDE) is a strong functional and positional Alzheimer’s disease (AD) candidate gene, which has shown significant association in some studies but not in others. Our purpose was to thoroughly evaluate IDE to determine if it has functional variants that show replicable association with AD.
    Methods: We first searched for putative functional variants in 269 AD and 252 control subjects by analyzing 40 amplicons containing all (9501 bp) of the conserved IDE DNA (>70% rodent vs. human) in IDE exons, 3’ and 5’ flanks (10 kb each), and several highly conserved introns. After genotyping, we used RT-PCR to analyze mRNA extracted from the cerebella of 162 subjects.
    Results: Only 15 of the 63 variants found in conserved DNA had minor allele frequencies >1%. Remarkably, 7 of these showed association at p < 0.25 in an exploratory series of 445 AD and 422 control subjects. These 7 variants formed 5 haplotypes with frequencies over 1% that comprised 97% of all haplotypes. Of the 5 haplotypes, 3 were protective and 2 were risky, and they showed significant association with AD in the exploratory series (nominal global p = 0.007). The same 5 major haplotypes were observed in a follow up series (857 AD, 957 CON) where they had the same effects (global p = 0.004). The 3 protective haplotypes pair to form 8 genotypes likely to be protective but too rare to analyze individually so this entire set of genotypes was used as a referent group and compared to the 5 remaining common genotypes. Logistic regression using age, ApoE, and gender as covariates showed 4 of the 5 genotypes were risky compared to the set of 8 protective pairs with a global significance of 0.007 in the exploratory series and 0.004 in the follow up series. Overall the set of risky IDE genotypes had an OR of 2.0 (1.52-2.65) with a PAR of 46% (30%-58%). The set of protective genotypes was associated with a significant (p=0.005) ~1.5-fold elevation of IDE mRNA.
    Conclusions: IDE genotypes associated with increased gene expression are associated with replicable reduction of risk for AD. IDE degrades Aß, which is associated with AD, so increased IDE expression should increase Aß degradation thereby reducing Aß and the risk of AD.

    Conference Organiser - ICMS Pty Ltd