Human Molecular Genetics Advance Access published online on August 30, 2007
Human Molecular Genetics, doi:10.1093/hmg/ddm244
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Genetic association of CTNNA3 with late-onset Alzheimer's disease in females
1 Bioresource Science Branch, Center for Bioresources, Brain Research Institute, Niigata University, Niigata 951-8585, Japan 2 Department of Geriatrics and Gerontology, Center for Asian Traditional Medicine, Tohoku University Graduate School of Medicine, Sendai 980-8574, Japan 3 Department of Psychiatry, Institute of Clinical Medicine, University of Tsukuba, Tsukuba 305-8575, Japan 4 Imagawa Clinic, Fukushima-ku, Osaka 553-0003, Japan 5 Department of Alzheimer's Disease Research, National Institute for Longevity Sciences, National Center for Geriatrics and Gerontology, Obu 474-8522, Japan 6 Department of Neurology, Neuroscience and Biophysiological Science, Hirosaki University, School of Medicine, Hirosaki 036-8562, Japan 7 Division of Clinical Research, Kurihama Alcoholism Center, National Hospital Organization, Yokosuka 239-0841, Japan 8 Department of Biological Regulation, Section of Environment and Health Science, Faculty of Medicine, Tottori University, Yonago 683-8503, Japan 9 Departments of Pathology and Pathological Neuroscience, Brain Research Institute, Niigata University, Niigata 951-8585, Japan 10 Department of Medical Informatics, Niigata University, Niigata 951-8520, Japan 11 National Center for Neurology and Psychiatry, Kodaira 187-8502, Japan 12 Department of Neuropathology, Faculty of Medicine, University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan
* To whom correspondence should be addressed: Address: 1-757 Asahimachi, Chuo-ku, Niigata 951-8585, Japan. TEL: +81-25-227-2343, Fax: +81-25-227-0793, E-mail: ryosun{at}bri.niigata-u.ac.jp (R. Kuwano)
Received July 18, 2007; Revised August 22, 2007; Accepted August 22, 2007
Alzheimer's disease (AD), the most common form of dementia in the elderly, was found to exhibit a trend toward a higher risk in females than in males through epidemiological studies. Therefore, we hypothesized that gender-related genetic risks could exist. To reveal ones for late-onset AD (LOAD), we extended our previous genetic work on chromosome 10q (genomic region, 60–107 Mb), and single nucleotide polymorphism (SNP)-based genetic association analyses were performed on the same chromosomal region, where the existence of genetic risk factors for plasma Aß42 elevation in LOAD was implied on a linkage analysis. Two-step screening of 1140 SNPs was carried out using a total of 1408 subjects with the APOE-
.3*3 genotype: we first genotyped an exploratory sample set (LOAD, 363; control, 337), and then genotyped some associated SNPs in a validation sample set (LOAD, 336; control, 372). Seven SNPs, spanning about 38 kb, in intron 9 of CTNNA3. were found to show multiple-hit association with LOAD in females, and exhibited more significant association on Mantel-Haenszel test (allelic P.-valuesMH-F = 0.000005945–0.0007658). Multiple logistic regression analysis of a total of 2762 subjects (LOAD, 1313; controls, 1449) demonstrated that one of the seven SNPs directly interacted with the female gender, but not with the male gender. Furthermore, we found that this SNP exhibited no interaction with the APOE-4. allele. Our data suggest that CTNNA3. may affect LOAD onset through a female-specific mechanism independent of the APOE-4. allele.
Present address is Risk Management Office, Niigata University Medical and Dental Hospital, Niigata 951-8520, Japan
Present address is Planning Office, Faculty of Life and Medical Sciences, Doshisha University, Kyoto 619-0225, Japan
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