Concordant association of insulin degrading enzyme gene (IDE) variants with IDE mRNA, Abeta, and Alzheimer's disease
<div> <h3>Background</h3> <p>The insulin-degrading enzyme gene (<em>IDE</em>) is a strong functional and positional candidate for late onset Alzheimer's disease (LOAD).</p> </div> <div> <h3>Methodology/Principal Findings</h3> <...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Journal article |
| Language: | English |
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Public Library of Science
2010
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| _version_ | 1826268968272265216 |
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| author | Belbin, O Zou, F Allen, M Ertekin-Taner, N Ansari, M Wilcox, S Kashino, MR Ma, L Younkin, L Younkin, S Younkin, C Dincman, T Howard, M Howell, C Stanton, C Watson, C 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, P Mann, D Smith, A Beaumont, H Warden, D Holmes, C Heun, R Kölsch, H Kalsheker, N Pankratz, V Dickson, D Graff-Radford, N Petersen, R Wright, A Younkin, S Morgan, K |
| author_facet | Belbin, O Zou, F Allen, M Ertekin-Taner, N Ansari, M Wilcox, S Kashino, MR Ma, L Younkin, L Younkin, S Younkin, C Dincman, T Howard, M Howell, C Stanton, C Watson, C 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, P Mann, D Smith, A Beaumont, H Warden, D Holmes, C Heun, R Kölsch, H Kalsheker, N Pankratz, V Dickson, D Graff-Radford, N Petersen, R Wright, A Younkin, S Morgan, K |
| author_sort | Belbin, O |
| collection | OXFORD |
| description | <div> <h3>Background</h3> <p>The insulin-degrading enzyme gene (<em>IDE</em>) is a strong functional and positional candidate for late onset Alzheimer's disease (LOAD).</p> </div> <div> <h3>Methodology/Principal Findings</h3> <p>We examined conserved regions of <em>IDE</em> 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 <em>IDE</em> transcript levels in samples from 194 LOAD cerebella. The strongest, rs6583817, which has not previously been reported, showed unequivocal association (p = 1.5×10<sup>−8</sup>, fold-increase = 2.12,); the eleven haplotypes were also significantly associated with transcript levels (global p = 0.003). Using an <em>in vitro</em> 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 (ß = −0.124, 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 <em>IDE</em> haplotypes (global p = 0.02) also showed significant association.</p> </div> <div> <h3>Conclusions</h3> <p>Thus, a previously unreported variant unequivocally associated with increased <em>IDE</em> expression was also associated with reduced plasma Aß40 and decreased LOAD susceptibility. Genetic association between LOAD and <em>IDE</em> 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.</p> </div> |
| first_indexed | 2024-03-06T21:17:40Z |
| format | Journal article |
| id | oxford-uuid:40582ee9-907d-4f60-b941-1597851044a4 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-06T21:17:40Z |
| publishDate | 2010 |
| publisher | Public Library of Science |
| record_format | dspace |
| spelling | oxford-uuid:40582ee9-907d-4f60-b941-1597851044a42022-03-26T14:37:26ZConcordant association of insulin degrading enzyme gene (IDE) variants with IDE mRNA, Abeta, and Alzheimer's diseaseJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:40582ee9-907d-4f60-b941-1597851044a4EnglishSymplectic Elements at OxfordPublic Library of Science2010Belbin, OZou, FAllen, MErtekin-Taner, NAnsari, MWilcox, SKashino, MRMa, LYounkin, LYounkin, SYounkin, CDincman, THoward, MHowell, CStanton, CWatson, CCrump, MVitart, VHayward, CHastie, NRudan, ICampbell, HPolasek, OBrown, KPassmore, PCraig, DMcGuinness, BTodd, SKehoe, PMann, DSmith, ABeaumont, HWarden, DHolmes, CHeun, RKölsch, HKalsheker, NPankratz, VDickson, DGraff-Radford, NPetersen, RWright, AYounkin, SMorgan, K<div> <h3>Background</h3> <p>The insulin-degrading enzyme gene (<em>IDE</em>) is a strong functional and positional candidate for late onset Alzheimer's disease (LOAD).</p> </div> <div> <h3>Methodology/Principal Findings</h3> <p>We examined conserved regions of <em>IDE</em> 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 <em>IDE</em> transcript levels in samples from 194 LOAD cerebella. The strongest, rs6583817, which has not previously been reported, showed unequivocal association (p = 1.5×10<sup>−8</sup>, fold-increase = 2.12,); the eleven haplotypes were also significantly associated with transcript levels (global p = 0.003). Using an <em>in vitro</em> 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 (ß = −0.124, 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 <em>IDE</em> haplotypes (global p = 0.02) also showed significant association.</p> </div> <div> <h3>Conclusions</h3> <p>Thus, a previously unreported variant unequivocally associated with increased <em>IDE</em> expression was also associated with reduced plasma Aß40 and decreased LOAD susceptibility. Genetic association between LOAD and <em>IDE</em> 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.</p> </div> |
| spellingShingle | Belbin, O Zou, F Allen, M Ertekin-Taner, N Ansari, M Wilcox, S Kashino, MR Ma, L Younkin, L Younkin, S Younkin, C Dincman, T Howard, M Howell, C Stanton, C Watson, C 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, P Mann, D Smith, A Beaumont, H Warden, D Holmes, C Heun, R Kölsch, H Kalsheker, N Pankratz, V Dickson, D Graff-Radford, N Petersen, R Wright, A Younkin, S Morgan, K Concordant association of insulin degrading enzyme gene (IDE) variants with IDE mRNA, Abeta, and Alzheimer's disease |
| title | Concordant association of insulin degrading enzyme gene (IDE) variants with IDE mRNA, Abeta, and Alzheimer's disease |
| title_full | Concordant association of insulin degrading enzyme gene (IDE) variants with IDE mRNA, Abeta, and Alzheimer's disease |
| title_fullStr | Concordant association of insulin degrading enzyme gene (IDE) variants with IDE mRNA, Abeta, and Alzheimer's disease |
| title_full_unstemmed | Concordant association of insulin degrading enzyme gene (IDE) variants with IDE mRNA, Abeta, and Alzheimer's disease |
| title_short | Concordant association of insulin degrading enzyme gene (IDE) variants with IDE mRNA, Abeta, and Alzheimer's disease |
| title_sort | concordant association of insulin degrading enzyme gene ide variants with ide mrna abeta and alzheimer s disease |
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