Alzheimers disease (AD), a common debilitating neurodegenerative disease, is a major public health problem in the United States because it affects almost 50% of the people after age 85. Although AD has been described since 1907, no cure or universally accepted effective treatment has been devised. Studying factors that play a role in risk and pathogenesis of LOAD may lead to development of new therapies and give an insight to the etiology of disease. Both genetic and environmental factors have been implicated in the etiology of AD. Twin studies have shown heredity to be a major causal factor in the development of LOAD. Despite the evidence for substantial genetic effect in the etiology of LOAD, the APOE*4 allele in the APOE gene is the only established risk factor in the development of LOAD. However, as the APOE*4 allele is neither necessary nor sufficient for the development of AD, this emphasizes the involvement of other genetic and/or environmental factors, which alone or in combination with APOE*4 can modify the risk of AD. Recently, linkage studies in multiplex families with LOAD have provided evidence for the existence of additional putative genes for AD on several chromosomes, including chromosome 10. A broad linkage peak encompassing >50 cM region between chromosome 10q21 and 10q25 has been implicated that influence both AD risk and age-at-onset (AAO). There are more than 300 genes in this broad genomic region of chromosome 10 and thus task for identifying the chromosome 10 gene is daunting. One approach is to focus on the known candidate genes in the region. There are number of promising candidate genes in this region that are involved in either in the production, processing or clearance of beta amyloid peptide and include choline acetyltransferase (CHAT), plasminogen activator, urinary (PLAU), insulin-degrading enzyme (IDE), hematopoietically expressed homeobox (HHEX), glutathione S-transferase, omega-1 (GSTO1), glutathione S-transferase, omega-2 (GSTO2), and protease, serine, 11 (PRSS11). In this study, we have examined the role of these genes under the linkage peak on chromosome 10 to assess their role with AD risk and AAO. Association studies for 14 markers were performed in a large case-control cohort comprising 1012 white LOAD subjects and 771 white control subjects. No significant associations were observed with any of the polymorphism examined in the IDE, HHEX, GSTO1, GSTO2 and PRSS11 genes. Of the 3 CHAT SNPs examined, we detected both allelic and genotypic association of the intron 9 polymorphism with AD risk. The rare AA genotype appears to confer a modest risk for the development of AD in a recessive fashion (OR: 2.37; p=0.007). In addition, we observed APOE-dependent effect of the CHAT exon 5 polymorphism with AD risk (OR=0.76; p=0.046). Although these associations are modest, they suggest the presence of putative functional variants in the CHAT gene or nearby genes. In the PLAU gene, we examined 3 tagSNPs and found a modest protective effect with one SNP in the 3 UTR (OR=0.71; p=0.02), which was confined to APOE*4 carriers (OR=0.58; p=0.02). In our analysis of the association of the candidate genes with AAO, suggestive association were observed only with the PLAU 3 UTR (p=0.10) and intron 9 (p=0.04) polymorphisms.
In summary, our data on a large number of AD cases and controls suggest that genetic variation in two positional candidate genes on chromosome 10 (PLAU and CHAT) may affect the risk and AAO of LOAD.
| Identifer | oai:union.ndltd.org:PITT/oai:PITTETD:etd-03242005-202137 |
| Date | 09 June 2005 |
| Creators | Ozturk, Ayla |
| Contributors | Candace M. Kammerer, Ph.D., M. Ilyas Kamboh, Ph.D, advisor, David N. Finegold, M.D., Robert E. Ferrell, Ph.D |
| Publisher | University of Pittsburgh |
| Source Sets | University of Pittsburgh |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.library.pitt.edu/ETD/available/etd-03242005-202137/ |
| Rights | unrestricted, I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to University of Pittsburgh or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
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