The University of Southampton
University of Southampton Institutional Repository

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.
1932-6203
e8764
Carrasquillo, Minerva M.
99f2da0d-0d7e-4f96-82a6-198a7d128521
Belbin, Olivia
63ea2667-9a3b-4430-9aa0-760eba028c1a
Zou, Fanggeng
0aa1ecce-ef18-489c-93c1-4336ea1e73b5
Allen, Mariet
83775fc7-465b-472c-8adf-a782aa315fec
Ertekin-Taner, Nilufer
5593d6a4-314a-4091-96b8-05ca199f424f
Ansari, Morad
b4831f76-cd33-4ba7-91bb-393d8acdc137
Wilcox, Samantha L.
b76dd713-972b-4558-88a9-ee1484942ee1
Kashino, Mariah R.
70053dad-a915-404a-9e50-635b4f7e1d78
Ma, Li
1ba2adc7-e4d8-4a7b-8cfd-10d9ff41564b
Younkin, Linda H.
435e42cd-4138-4670-8821-37cd68fad133
Younkin, Samuel G.
3074ca27-8cd8-4649-9c10-6e3b920e4f50
Younkin, Curtis S.
2095850b-0a07-4f1f-8586-b3bdc774cab8
Dincman, Toros A.
7c36e789-5d74-4a94-874a-24c6bcd63085
Howard, Melissa E.
44536b83-0639-4b92-85f2-81f8972c1b6e
Howell, Chanley C.
e61c73ea-21e3-4c3a-8ba4-98f705a98813
Stanton, Chloe M.
e49a140e-86a0-46f4-a109-fde65288d457
Watson, Christopher M.
83b46b74-e6a1-4ee9-8078-c69693de008a
Crump, Michael
cd35778b-d3e7-427f-90d3-3e70c140acda
Vitart, Veronique
30073df8-6255-430e-a143-d600fa48bacd
Hayward, Caroline
8b58ae74-401a-4306-8b8f-c8414485131c
Hastie, Nicholas D.
841dc8ec-2d5c-4426-a94e-0b46fb0e68ea
Rudan, Igor
89b94981-36be-463c-9068-fd2140b05903
Campbell, Harry
7ef78bec-0f39-477c-baa5-a773d59aa7c7
Polasek, Ozren
e5975087-c8c1-4938-9caf-c9212d41ff08
Brown, Kristelle
ad4cf1d3-7aff-4fc0-9b98-61f76c94297d
Passmore, Peter
175afd4d-532f-4340-b40b-ce5f4b7e8945
Craig, David
23276bd6-127b-4565-950e-8f42d299bc2c
McGuinness, Bernadette
90a0a19e-ed7f-4fe0-8860-74ee73ff037f
Todd, Stephen
826c1117-8f6d-4435-aa40-f345509d7e6e
Kehoe, Patrick G.
c3d54052-f508-4091-86ce-ec4727ef3c9a
Mann, David M.
225e5082-e812-4ff4-87ad-a50801ef4b9e
Smith, A. David
df633949-c1d9-461d-bb86-bceffa024adb
Beaumont, Helen
3f9afb3a-d579-4787-a883-c98490330e4b
Warden, Donald
ff174c01-f0f9-4d84-b799-521889dc7b86
Holmes, Clive
ada5abf3-8459-4cf7-be40-3f4e9391cc96
Heun, Reinhard
6de18a82-a77d-46ff-a587-c3f505f7211f
Kölsch, Heike
ad3c753d-f258-4582-ba0c-9f434cf44be8
Kalsheker, Noor
91f67e98-ae72-4acf-97c7-ff89423c5b57
Pankratz, V. Shane
bd3ea90e-e906-41ed-846b-d012c6c30610
Dickson, Dennis W.
9e5d8168-d8a4-4540-99d3-2decc5fef8e0
Graff-Radford, Neill R.
2d4ba46e-118f-4ed9-8f23-a8829c7a8da6
Petersen, Ronald C.
3655bd22-ce59-42d8-a44c-9959d2d0618f
Wright, Alan F.
7efbb151-a98c-4398-b69f-92d5cac84f50
Younkin, Steven G.
43cbe681-3b39-446d-8671-5e44c2cbd77d
Morgan, Kevin
f4a865c9-f8cc-443c-a2e7-3e3ac5a8cf85
Carrasquillo, Minerva M.
99f2da0d-0d7e-4f96-82a6-198a7d128521
Belbin, Olivia
63ea2667-9a3b-4430-9aa0-760eba028c1a
Zou, Fanggeng
0aa1ecce-ef18-489c-93c1-4336ea1e73b5
Allen, Mariet
83775fc7-465b-472c-8adf-a782aa315fec
Ertekin-Taner, Nilufer
5593d6a4-314a-4091-96b8-05ca199f424f
Ansari, Morad
b4831f76-cd33-4ba7-91bb-393d8acdc137
Wilcox, Samantha L.
b76dd713-972b-4558-88a9-ee1484942ee1
Kashino, Mariah R.
70053dad-a915-404a-9e50-635b4f7e1d78
Ma, Li
1ba2adc7-e4d8-4a7b-8cfd-10d9ff41564b
Younkin, Linda H.
435e42cd-4138-4670-8821-37cd68fad133
Younkin, Samuel G.
3074ca27-8cd8-4649-9c10-6e3b920e4f50
Younkin, Curtis S.
2095850b-0a07-4f1f-8586-b3bdc774cab8
Dincman, Toros A.
7c36e789-5d74-4a94-874a-24c6bcd63085
Howard, Melissa E.
44536b83-0639-4b92-85f2-81f8972c1b6e
Howell, Chanley C.
e61c73ea-21e3-4c3a-8ba4-98f705a98813
Stanton, Chloe M.
e49a140e-86a0-46f4-a109-fde65288d457
Watson, Christopher M.
83b46b74-e6a1-4ee9-8078-c69693de008a
Crump, Michael
cd35778b-d3e7-427f-90d3-3e70c140acda
Vitart, Veronique
30073df8-6255-430e-a143-d600fa48bacd
Hayward, Caroline
8b58ae74-401a-4306-8b8f-c8414485131c
Hastie, Nicholas D.
841dc8ec-2d5c-4426-a94e-0b46fb0e68ea
Rudan, Igor
89b94981-36be-463c-9068-fd2140b05903
Campbell, Harry
7ef78bec-0f39-477c-baa5-a773d59aa7c7
Polasek, Ozren
e5975087-c8c1-4938-9caf-c9212d41ff08
Brown, Kristelle
ad4cf1d3-7aff-4fc0-9b98-61f76c94297d
Passmore, Peter
175afd4d-532f-4340-b40b-ce5f4b7e8945
Craig, David
23276bd6-127b-4565-950e-8f42d299bc2c
McGuinness, Bernadette
90a0a19e-ed7f-4fe0-8860-74ee73ff037f
Todd, Stephen
826c1117-8f6d-4435-aa40-f345509d7e6e
Kehoe, Patrick G.
c3d54052-f508-4091-86ce-ec4727ef3c9a
Mann, David M.
225e5082-e812-4ff4-87ad-a50801ef4b9e
Smith, A. David
df633949-c1d9-461d-bb86-bceffa024adb
Beaumont, Helen
3f9afb3a-d579-4787-a883-c98490330e4b
Warden, Donald
ff174c01-f0f9-4d84-b799-521889dc7b86
Holmes, Clive
ada5abf3-8459-4cf7-be40-3f4e9391cc96
Heun, Reinhard
6de18a82-a77d-46ff-a587-c3f505f7211f
Kölsch, Heike
ad3c753d-f258-4582-ba0c-9f434cf44be8
Kalsheker, Noor
91f67e98-ae72-4acf-97c7-ff89423c5b57
Pankratz, V. Shane
bd3ea90e-e906-41ed-846b-d012c6c30610
Dickson, Dennis W.
9e5d8168-d8a4-4540-99d3-2decc5fef8e0
Graff-Radford, Neill R.
2d4ba46e-118f-4ed9-8f23-a8829c7a8da6
Petersen, Ronald C.
3655bd22-ce59-42d8-a44c-9959d2d0618f
Wright, Alan F.
7efbb151-a98c-4398-b69f-92d5cac84f50
Younkin, Steven G.
43cbe681-3b39-446d-8671-5e44c2cbd77d
Morgan, Kevin
f4a865c9-f8cc-443c-a2e7-3e3ac5a8cf85

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.

Other
fetchObject.action_uri=info_doi%2F10.1371%2Fjournal.pone.0008764&representation=PDF - Version of Record
Available under License Other.
Download (386kB)

More information

Published date: 19 January 2010

Identifiers

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

Catalogue record

Date deposited: 14 May 2010 10:20
Last modified: 20 Feb 2019 01:36

Export record

Altmetrics

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

University divisions

Download statistics

Downloads from ePrints over the past year. Other digital versions may also be available to download e.g. from the publisher's website.

View more statistics

Atom RSS 1.0 RSS 2.0

Contact ePrints Soton: eprints@soton.ac.uk

ePrints Soton supports OAI 2.0 with a base URL of https://eprints.soton.ac.uk/cgi/oai2

This repository has been built using EPrints software, developed at the University of Southampton, but available to everyone to use.

We use cookies to ensure that we give you the best experience on our website. If you continue without changing your settings, we will assume that you are happy to receive cookies on the University of Southampton website.

×