Association studies between risk for late-onset Alzheimer's disease and variants in insulin degrading enzyme.

Abstract

Linkage studies have suggested there is a susceptibility gene for late onset Alzheimer's disease (LOAD) in a broad region of chromosome 10. A strong positional and biological candidate is the gene encoding the insulin-degrading enzyme (IDE), a protease involved in the catabolism of Abeta. However, previous association studies have produced inconsistent results. To systematically evaluate the role of variation in IDE in the risk for LOAD, we genotyped 18 SNPs spanning a 276 kb region in and around IDE, including three "tagging" SNPs identified in an earlier study. We used four case-control series with a total of 1,217 cases and 1,257 controls. One SNP (IDE_7) showed association in two samples (P-value = 0.0066, and P = 0.026, respectively), but this result was not replicated in the other two series. None of the other SNPs showed association with LOAD in any of the tested samples. Haplotypes, constructed from the three tagging SNPs, showed no globally significant association. In the UK2 series, the CTA haplotype was over-represented in cases (P = 0.046), and in the combined data set, the CCG haplotype was more frequent in controls (P = 0.015). However, these weak associations observed in our series were in the opposite direction to the results in previous studies. Although our results are not universally negative, we were unable to replicate the results of previous studies and conclude that common variants or haplotypes of these variants in IDE are not major risk factors for LOAD.

• Authors: Petra Nowotny, Anthony L Hinrichs, Scott Smemo, John S K Kauwe, Taylor Maxwell, Peter Holmans, Marian Hamshere, Dragana Turic, Luke Jehu, Paul Hollingworth, Pamela Moore, Leslie Bryden, Amanda Myers, Lisa M Doil, Kristina M Tacey, Alison M Gibson, Ian G McKeith, Robert H Perry, Chris M Morris, Leon Thal, John C Morris, Michael C O'Donovan, Simon Lovestone, Andrew Grupe, John Hardy, Michael J Owen, Julie Williams, Alison Goate
• Journal: American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics (Am J Med Genet B Neuropsychiatr Genet) Vol. 136B Issue 1 Pg. 62-8 (Jul 05 2005) ISSN: 1552-4841 [Print] United States
• PMID: 15858813 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)
• Copyright: Copyright 2005 Wiley-Liss, Inc.

Chemical References

• Apolipoproteins E
• Genetic Markers
• Insulysin

Topics

• Alleles
• Alzheimer Disease (enzymology, genetics)
• Apolipoproteins E (genetics)
• Case-Control Studies
• Female
• Gene Frequency
• Genetic Markers (genetics)
• Genotype
• Haplotypes
• Humans
• Insulysin (genetics)
• Linkage Disequilibrium
• Male
• Polymorphism, Single Nucleotide
• Risk Factors