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

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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 = 1.5×10 ⁻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 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 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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Most cited references 41

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Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families.

E H Corder, A M Saunders, W J Strittmatter … (1993)

The apolipoprotein E type 4 allele (APOE-epsilon 4) is genetically associated with the common late onset familial and sporadic forms of Alzheimer's disease (AD). Risk for AD increased from 20% to 90% and mean age at onset decreased from 84 to 68 years with increasing number of APOE-epsilon 4 alleles in 42 families with late onset AD. Thus APOE-epsilon 4 gene dose is a major risk factor for late onset AD and, in these families, homozygosity for APOE-epsilon 4 was virtually sufficient to cause AD by age 80.

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Systematic meta-analyses of Alzheimer disease genetic association studies: the AlzGene database.

Lars Bertram, Matthew B. McQueen, Kristina Mullin … (2007)

The past decade has witnessed hundreds of reports declaring or refuting genetic association with putative Alzheimer disease susceptibility genes. This wealth of information has become increasingly difficult to follow, much less interpret. We have created a publicly available, continuously updated database that comprehensively catalogs all genetic association studies in the field of Alzheimer disease (http://www.alzgene.org). We performed systematic meta-analyses for each polymorphism with available genotype data in at least three case-control samples. In addition to identifying the epsilon4 allele of APOE and related effects, we pinpointed over a dozen potential Alzheimer disease susceptibility genes (ACE, CHRNB2, CST3, ESR1, GAPDHS, IDE, MTHFR, NCSTN, PRNP, PSEN1, TF, TFAM and TNF) with statistically significant allelic summary odds ratios (ranging from 1.11-1.38 for risk alleles and 0.92-0.67 for protective alleles). Our database provides a powerful tool for deciphering the genetics of Alzheimer disease, and it serves as a potential model for tracking the most viable gene candidates in other genetically complex diseases.

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Insulin-degrading enzyme regulates the levels of insulin, amyloid beta-protein, and the beta-amyloid precursor protein intracellular domain in vivo.

Wesley Farris, Stefan Mansourian, Yang Chang … (2003)

Two substrates of insulin-degrading enzyme (IDE), amyloid beta-protein (Abeta) and insulin, are critically important in the pathogenesis of Alzheimer's disease (AD) and type 2 diabetes mellitus (DM2), respectively. We previously identified IDE as a principal regulator of Abeta levels in neuronal and microglial cells. A small chromosomal region containing a mutant IDE allele has been associated with hyperinsulinemia and glucose intolerance in a rat model of DM2. Human genetic studies have implicated the IDE region of chromosome 10 in both AD and DM2. To establish whether IDE hypofunction decreases Abeta and insulin degradation in vivo and chronically increases their levels, we characterized mice with homozygous deletions of the IDE gene (IDE --). IDE deficiency resulted in a >50% decrease in Abeta degradation in both brain membrane fractions and primary neuronal cultures and a similar deficit in insulin degradation in liver. The IDE -- mice showed increased cerebral accumulation of endogenous Abeta, a hallmark of AD, and had hyperinsulinemia and glucose intolerance, hallmarks of DM2. Moreover, the mice had elevated levels of the intracellular signaling domain of the beta-amyloid precursor protein, which was recently found to be degraded by IDE in vitro. Together with emerging genetic evidence, our in vivo findings suggest that IDE hypofunction may underlie or contribute to some forms of AD and DM2 and provide a mechanism for the recently recognized association among hyperinsulinemia, diabetes, and AD.

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Author and article information

Contributors

: Role: Editor

Journal

Journal ID (nlm-ta): PLoS One

Journal ID (publisher-id): plos

Journal ID (pmc): plosone

Title: PLoS ONE

Publisher: Public Library of Science (San Francisco, USA )

ISSN (Electronic): 1932-6203

Publication date Collection: 2010

Publication date (Electronic): 19 January 2010

Volume: 5

Issue: 1

Electronic Location Identifier: e8764

Affiliations

[1 ]Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, Florida, United States of America

[2 ]Medical Research Council (MRC) Human Genetics Unit, The Institute of Genetics and Molecular Medicine, Western General Hospital, Edinburgh, United Kingdom

[3 ]Department of Neurology, Mayo Clinic College of Medicine, Jacksonville, Florida, United States of America

[4 ]Department of Public Health Sciences, University of Edinburgh Medical School, Edinburgh, Scotland, United Kingdom

[5 ]Croatian Centre for Global Health, University of Split Medical School, Split, Croatia

[6 ]Centre for Clinical Medical Research, University Hospital “Sestre Milosrdnice”, Zagreb, Croatia

[7 ]School of Molecular Medical Sciences, Institute of Genetics, Queen's Medical Centre, University of Nottingham, Nottingham, United Kingdom

[8 ]Division of Psychiatry and Neuroscience, School of Medicine and Dentistry, Queen's University Belfast, Belfast, Northern Ireland, United Kingdom

[9 ]Department of Clinical Science at North Bristol, University of Bristol, Frenchay Hospital, Bristol, United Kingdom

[10 ]Greater Manchester Neurosciences Centre, University of Manchester, Manchester, United Kingdom

[11 ]Oxford Project to Investigate Memory and Ageing (OPTIMA), University Department of Physiology, Anatomy and Genetics, Oxford, United Kingdom

[12 ]Memory Assessment and Research Centre, University of Southampton, Southampton, United Kingdom

[13 ]Division of Neuroscience, University of Birmingham, Birmingham, United Kingdom

[14 ]Department of Psychiatry, University of Bonn, Bonn, Germany

[15 ]Department of Biostatistics, Mayo Clinic and Mayo Foundation, Rochester, Minnesota, United States of America

[16 ]Department of Neurology and the Mayo Alzheimer Disease Research Center, Mayo Clinic College of Medicine, Rochester, Minnesota, United States of America

National Institutes of Health, United States of America

Author notes

* E-mail: younkin.steven@ 123456mayo.edu

Conceived and designed the experiments: MMC OB FZ MA LHY AW SGY KM. Performed the experiments: MMC OB FZ MA MA SLW MRK LM LHY TAD MEH CCH CMS CMW MC VV CH KB. Analyzed the data: MMC OB FZ MA NET MA SLW MRK SGY CSY VV CH VSP SGY KM. Contributed reagents/materials/analysis tools: MMC NH IR HC OP PP DC BM ST PGK DM ADS HB DW CH RH HK NK DWD NRGR RCP SGY KM. Wrote the paper: MMC OB FZ MA NET SGY KM. Principal investigator: SGY KM.

[¤]

Current address: Gen-info Ltd., Zagreb, Croatia

Article

Publisher ID: 09-PONE-RA-13657R1

DOI: 10.1371/journal.pone.0008764

PMC ID: 2808243

PubMed ID: 20098734

SO-VID: 7b21f83c-39bf-4c56-a2f4-15f35200b680

Copyright © 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.

History

Date received : 19 October 2009

Date accepted : 17 December 2009

Page count

Pages: 12

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

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Abstract

Background

Methodology/Principal Findings

Conclusions

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PLOS Climate

Most cited references 41

Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families.

Systematic meta-analyses of Alzheimer disease genetic association studies: the AlzGene database.

Insulin-degrading enzyme regulates the levels of insulin, amyloid beta-protein, and the beta-amyloid precursor protein intracellular domain in vivo.

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Cited by 20