Concordant association of insulin degrading enzyme gene (IDE) variants with IDE mRNA, Abeta, and Alzheimer's disease.

PloS One
Minerva M CarrasquilloKevin Morgan

Abstract

The insulin-degrading enzyme gene (IDE) is a strong functional and positional candidate for late onset Alzheimer's disease (LOAD). 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 = 1.5x10(-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 Abeta40 levels (ss = -0.124, p = 0.011) and total measured plasma Abeta levels (b = -0.130, p = 0.009). Finally, rs6583817 was associated with decreased risk of LOAD in 3,891...Continue Reading

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Methods Mentioned

BETA
transfection
PCR
genotyping
Assay
ELISA

Software Mentioned

AlzGene
stats
GenABEL
haplo
PLINK
em
VISTA Genome Browser
HaploView
ABI PRISM® SDS
Navigatorâ¢

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