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

Concordant association of insulin degrading enzyme gene (IDE) variants with IDE mRNA, abeta, and alzheimer's disease.
Concordant association of insulin degrading enzyme gene (IDE) variants with IDE mRNA, abeta, and alzheimer's disease.
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 = 1.5x10(-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 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 Ass40 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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Carrasquillo, Minerva M., Belbin, Olivia, Zou, Fanggeng, Allen, Mariet, Ertekin-Taner, Nilufer, Ansari, Morad, Wilcox, Samantha L., Kashino, Mariah R., Ma, Li, Younkin, Linda H., Younkin, Samuel G., Younkin, Curtis S., Dincman, Toros A., Howard, Melissa E., Howell, Chanley C., Stanton, Chloe M., Watson, Christopher M., Crump, Michael, Vitart, Veronique, Hayward, Caroline, Hastie, Nicholas D., Rudan, Igor, Campbell, Harry, Polasek, Ozren, Brown, Kristelle, Passmore, Peter, Craig, David, McGuinness, Bernadette, Todd, Stephen, Kehoe, Patrick G., Mann, David M., Smith, A. David, Beaumont, Helen, Warden, Donald, Holmes, Clive, Heun, Reinhard, Kölsch, Heike, Kalsheker, Noor, Pankratz, V. Shane, Dickson, Dennis W., Graff-Radford, Neill R., Petersen, Ronald C., Wright, Alan F., Younkin, Steven G. and Morgan, Kevin (2010) Concordant association of insulin degrading enzyme gene (IDE) variants with IDE mRNA, abeta, and alzheimer's disease. PLoS ONE, 5 (1), e8764. (doi:10.1371/journal.pone.0008764).

Record type: Article

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 = 1.5x10(-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 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 Ass40 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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Published date: 19 January 2010
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Identifiers

Local EPrints ID: 152267
URI: http://eprints.soton.ac.uk/id/eprint/152267
DOI: doi:10.1371/journal.pone.0008764
ISSN: 1932-6203
PURE UUID: 3d690209-7836-46e2-8592-381eab2cc949
ORCID for Clive Holmes: ORCID iD orcid.org/0000-0003-1999-6912

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Date deposited: 14 May 2010 10:20
Last modified: 14 Mar 2024 02:43

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Contributors

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

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