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

被引：44

作者：

Carrasquillo, Minerva M. ^{[1
]}

Belbin, Olivia ^{[1
]}

Zou, Fanggeng ^{[1
]}

Allen, Mariet ^{[1
,2
]}

Ertekin-Taner, Nilufer ^{[1
,3
]}

Ansari, Morad ^{[2
]}

Wilcox, Samantha L. ^{[1
]}

Kashino, Mariah R. ^{[1
]}

Ma, Li ^{[1
]}

Younkin, Linda H. ^{[1
]}

Younkin, Samuel G. ^{[1
]}

Younkin, Curtis S. ^{[1
]}

Dincman, Toros A. ^{[1
]}

Howard, Melissa E. ^{[1
]}

Howell, Chanley C. ^{[1
]}

Stanton, Chloe M. ^{[1
]}

Watson, Christopher M. ^{[1
]}

Crump, Michael ^{[1
]}

Vitart, Veronique ^{[2
]}

Hayward, Caroline ^{[2
]}

Hastie, Nicholas D. ^{[2
]}

Rudan, Igor ^{[4
,5
,6
]}

Campbell, Harry ^{[4
]}

Polasek, Ozren ^{[4
,6
]}

Brown, Kristelle ^{[7
]}

Passmore, Peter ^{[8
]}

Craig, David ^{[8
]}

McGuinness, Bernadette ^{[8
]}

Todd, Stephen ^{[8
]}

Kehoe, Patrick G. ^{[9
]}

Mann, David M. ^{[10
]}

Smith, A. David ^{[11
]}

Beaumont, Helen ^{[11
]}

Warden, Donald ^{[11
]}

Holmes, Clive ^{[12
]}

Heun, Reinhard ^{[13
]}

Koelsch, Heike ^{[14
]}

Kalsheker, Noor ^{[7
]}

Pankratz, V. Shane ^{[15
]}

Dickson, Dennis W. ^{[1
]}

Graff-Radford, Neill R. ^{[3
]}

Petersen, Ronald C. ^{[16
,17
]}

Wright, Alan F. ^{[2
]}

Younkin, Steven G. ^{[1
]}

Morgan, Kevin ^{[7
]}

机构：

[1] Mayo Clin, Coll Med, Dept Neurosci, Jacksonville, FL 32224 USA

[2] Western Gen Hosp, MRC, Human Genet Unit, Inst Genet & Mol Med, Edinburgh EH4 2XU, Midlothian, Scotland

[3] Mayo Clin, Dept Neurol, Coll Med, Jacksonville, FL 32224 USA

[4] Univ Edinburgh, Sch Med, Dept Publ Hlth Sci, Edinburgh, Midlothian, Scotland

[5] Univ Split, Sch Med, Croatian Ctr Global Hlth, Split, Croatia

[6] Univ Hosp Sestre Milosrdnice, Ctr Clin Med Res, Zagreb, Croatia

[7] Univ Nottingham, Inst Genet, Sch Mol Med Sci, Queens Med Ctr, Nottingham NG7 2RD, England

[8] Queens Univ Belfast, Sch Med & Dent, Div Psychiat & Neurosci, Belfast, Antrim, North Ireland

[9] Univ Bristol, Frenchay Hosp, Dept Clin Sci N Bristol, Bristol, Avon, England

[10] Univ Manchester, Greater Manchester Neurosci Ctr, Manchester, Lancs, England

[11] Univ Dept Physiol Anat & Genet, Oxford Project Investigate Memory & Ageing OPTIMA, Oxford, England

[12] Univ Southampton, Memory Assessment & Res Ctr, Southampton, Hants, England

[13] Univ Birmingham, Div Neurosci, Birmingham, W Midlands, England

[14] Univ Bonn, Dept Psychiat, D-5300 Bonn, Germany

[15] Mayo Clin & Mayo Fdn, Dept Biostat, Rochester, MN 55905 USA

[16] Mayo Clin, Coll Med, Dept Neurol, Rochester, MN USA

[17] Mayo Clin, Coll Med, Mayo Alzheimer Dis Res Ctr, Rochester, MN USA

来源：

PLOS ONE | 2010年 / 5卷 / 01期

基金：

英国医学研究理事会; 美国国家卫生研究院;

关键词：

BLOCK SPANNING IDE; APOLIPOPROTEIN-E; HAPLOTYPE BLOCK; IN-VIVO; EXTRACELLULAR LEVELS; WIDE ASSOCIATION; NO ASSOCIATION; ONSET; PROTEIN; RISK;

D O I：

10.1371/journal.pone.0008764

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页数：12

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