Concordant Association of Insulin Degrading Enzyme Gene (IDE) Variants with IDE mRNA, A beta, 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 Hayward; Nick 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 Koelsch; Noor Kalsheker; V. Shane Pankratz; Dennis W. Dickson; Neill R. Graff-Radford; Ronald C. Petersen; Alan F. Wright; Steven G. Younkin; Kevin Morgan

doi:10.1371/journal.pone.0008764

Concordant Association of Insulin Degrading Enzyme Gene (IDE) Variants with IDE mRNA, A beta, 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 HaywardNick 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 Koelsch, 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 journal › Article › peer-review

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 x 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 A beta 40 levels (beta = 20.124, p = 0.011) and total measured plasma A beta levels (b = 20.130, 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 A beta 40 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 language	English
Article number	e8764
Pages (from-to)	-
Number of pages	12
Journal	PLoS ONE
Volume	5
Issue number	1
DOIs	https://doi.org/10.1371/journal.pone.0008764
Publication status	Published - 19 Jan 2010

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10.1371/journal.pone.0008764

Concordant Association of Insulin Degrading Enzyme Gene (IDE) Variants with IDE mRNA, A beta, and Alzheimer's Disease
Copyright: © 2010 Carrasquillo et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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Carrasquillo, M. M., Belbin, O., Zou, F., Allen, M., Ertekin-Taner, N., Ansari, M., Wilcox, S. L., Kashino, M. R., Ma, L., Younkin, L. H., Younkin, S. G., Younkin, C. S., Dincman, T. A., Howard, M. E., Howell, C. C., Stanton, C. M., Watson, C. M., Crump, M., Vitart, V., ... Morgan, K. (2010). Concordant Association of Insulin Degrading Enzyme Gene (IDE) Variants with IDE mRNA, A beta, and Alzheimer's Disease. PLoS ONE, 5(1), -. Article e8764. https://doi.org/10.1371/journal.pone.0008764

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title = "Concordant Association of Insulin Degrading Enzyme Gene (IDE) Variants with IDE mRNA, A beta, and Alzheimer's Disease",

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 x 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 A beta 40 levels (beta = 20.124, p = 0.011) and total measured plasma A beta levels (b = 20.130, 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 A beta 40 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.",

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

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month = jan,

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doi = "10.1371/journal.pone.0008764",

language = "English",

volume = "5",

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Carrasquillo, MM, Belbin, O, Zou, F, Allen, M, Ertekin-Taner, N, Ansari, M, Wilcox, SL, Kashino, MR, Ma, L, Younkin, LH, Younkin, SG, Younkin, CS, Dincman, TA, Howard, ME, Howell, CC, Stanton, CM, Watson, CM, Crump, M, Vitart, V, Hayward, C, Hastie, N, Rudan, I , Campbell, H, Polasek, O, Brown, K, Passmore, P, Craig, D, McGuinness, B, Todd, S, Kehoe, PG, Mann, DM, Smith, AD, Beaumont, H, Warden, D, Holmes, C, Heun, R, Koelsch, H, Kalsheker, N, Pankratz, VS, Dickson, DW, Graff-Radford, NR, Petersen, RC, Wright, AF, Younkin, SG & Morgan, K 2010, 'Concordant Association of Insulin Degrading Enzyme Gene (IDE) Variants with IDE mRNA, A beta, and Alzheimer's Disease', PLoS ONE, vol. 5, no. 1, e8764, pp. -. https://doi.org/10.1371/journal.pone.0008764

TY - JOUR

T1 - Concordant Association of Insulin Degrading Enzyme Gene (IDE) Variants with IDE mRNA, A beta, 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, Nick

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 - Koelsch, 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 x 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 A beta 40 levels (beta = 20.124, p = 0.011) and total measured plasma A beta levels (b = 20.130, 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 A beta 40 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 x 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 A beta 40 levels (beta = 20.124, p = 0.011) and total measured plasma A beta levels (b = 20.130, 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 A beta 40 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

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JF - PLoS ONE

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ER -

Concordant Association of Insulin Degrading Enzyme Gene (IDE) Variants with IDE mRNA, A beta, and Alzheimer's Disease

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