TY - JOUR
T1 - Concordant association of Insulin Degrading Enzyme gene (IDE) Variants with IDE mRNA, Aß, and Alzheimer's disease
AU - Carrasquillo, Minerva M.
AU - Belbin, Olivia
AU - Zou, Fanggeng
AU - Allen, Mariet
AU - Ertekin-Taner, Nilufer
AU - Ansari, Morad
AU - Wilcox, Samantha L.
AU - Kashino, Mariah R.
AU - Ma, Li
AU - Younkin, Linda H.
AU - Younkin, Samuel G.
AU - Younkin, Curtis S.
AU - Dincman, Toros A.
AU - Howard, Melissa E.
AU - Howell, Chanley C.
AU - Stanton, Chloe M.
AU - Watson, Christopher M.
AU - Crump, Michael
AU - Vitart, Veronique
AU - Hayward, Caroline
AU - Hastie, Nicholas D.
AU - Rudan, Igor
AU - Campbell, Harry
AU - Polasek, Ozren
AU - Brown, Kristelle
AU - Passmore, Peter
AU - Craig, David
AU - McGuinness, Bernadette
AU - Todd, Stephen
AU - Kehoe, Patrick G.
AU - Mann, David M.
AU - Smith, A. David
AU - Beaumont, Helen
AU - Warden, Donald
AU - Holmes, Clive
AU - Heun, Reinhard
AU - Kölsch, Heike
AU - Kalsheker, Noor
AU - Pankratz, V. Shane
AU - Dickson, Dennis W.
AU - Graff-Radford, Neill R.
AU - Petersen, Ronald C.
AU - Wright, Alan F.
AU - Younkin, Steven G.
AU - Morgan, Kevin
PY - 2010/1/19
Y1 - 2010/1/19
N2 - 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.
AB - 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.
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U2 - 10.1371/journal.pone.0008764
DO - 10.1371/journal.pone.0008764
M3 - Article
C2 - 20098734
AN - SCOPUS:77649295213
SN - 1932-6203
VL - 5
JO - PloS one
JF - PloS one
IS - 1
M1 - e8764
ER -