Concordant association of Insulin Degrading Enzyme gene (IDE) Variants with IDE mRNA, Aß, and Alzheimer's disease

Minerva M. Carrasquillo, Olivia Belbin, Fanggeng Zou, Mariet Allen, Nilufer Ertekin-Taner, Morad Ansari, Samantha L. Wilcox, Mariah R. Kashino, Li Ma, Linda H. Younkin, Samuel G. Younkin, Curtis S. Younkin, Toros A. Dincman, Melissa E. Howard, Chanley C. Howell, Chloe M. Stanton, Christopher M. Watson, Michael Crump, Veronique Vitart, Caroline HaywardNicholas D. Hastie, Igor Rudan, Harry Campbell, Ozren Polasek, Kristelle Brown, Peter Passmore, David Craig, Bernadette McGuinness, Stephen Todd, Patrick G. Kehoe, David M. Mann, A. David Smith, Helen Beaumont, Donald Warden, Clive Holmes, Reinhard Heun, Heike Kölsch, Noor Kalsheker, V. Shane Pankratz, Dennis W. Dickson, Neill R. Graff-Radford, Ronald C. Petersen, Alan F. Wright, Steven G. Younkin, Kevin Morgan

Research output: Contribution to journalArticlepeer-review

36 Scopus citations

Abstract

Background: The insulin-degrading enzyme gene (IDE) is a strong functional and positional candidate for late onset Alzheimer's disease (LOAD). Methodology/Principal Findings: We examined conserved regions of IDE and its 10 kb flanks in 269 AD cases and 252 controls thereby identifying 17 putative functional polymorphisms. These variants formed eleven haplotypes that were tagged with ten variants. Four of these showed significant association with IDE transcript levels in samples from 194 LOAD cerebella. The strongest, rs6583817, which has not previously been reported, showed unequivocal association (p = 1.5 × 10-8, fold-increase = 2.12,); the eleven haplotypes were also significantly associated with transcript levels (global p = 0.003). Using an in vitro dual luciferase reporter assay, we found that rs6583817 increases reporter gene expression in Be(2)-C (p = 0.006) and HepG2 (p = 0.02) cell lines. Furthermore, using data from a recent genome-wide association study of two Croatian isolated populations (n = 1,879), we identified a proxy for rs6583817 that associated significantly with decreased plasma Aβ40 levels (β = -20.124, p = 0.011) and total measured plasma Aβ levels (b = -0.130, p = 0.009). Finally, rs6583817 was associated with decreased risk of LOAD in 3,891 AD cases and 3,605 controls. (OR = 0.87, p = 0.03), and the eleven IDE haplotypes (global p = 0.02) also showed significant association. Conclusions: Thus, a previously unreported variant unequivocally associated with increased IDE expression was also associated with reduced plasma Aβ40 and decreased LOAD susceptibility. Genetic association between LOAD and IDE has been difficult to replicate. Our findings suggest that targeted testing of expression SNPs (eSNPs) strongly associated with altered transcript levels in autopsy brain samples may be a powerful way to identify genetic associations with LOAD that would otherwise be difficult to detect.

Original languageEnglish (US)
Article numbere8764
JournalPloS one
Volume5
Issue number1
DOIs
StatePublished - Jan 19 2010

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

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