Journal Article

Genetic association of <i>CTNNA3</i> with late-onset Alzheimer's disease in females

Akinori Miyashita, Hiroyuki Arai, Takashi Asada, Masaki Imagawa, Etsuro Matsubara, Mikio Shoji, Susumu Higuchi, Katsuya Urakami, Akiyoshi Kakita, Hitoshi Takahashi, Shinichi Toyabe, Kohei Akazawa, Ichiro Kanazawa, Yasuo Ihara and Ryozo Kuwano

in Human Molecular Genetics

Volume 16, issue 23, pages 2854-2869
Published in print December 2007 | ISSN: 0964-6906
Published online August 2007 | e-ISSN: 1460-2083 | DOI: http://dx.doi.org/10.1093/hmg/ddm244
Genetic association of CTNNA3 with late-onset Alzheimer's disease in females

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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 the 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 Aβ42 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-ε3*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-ε4 allele. Our data suggest that CTNNA3 may affect LOAD through a female-specific mechanism independent of the APOE-ε4 allele.

Journal Article.  9959 words.  Illustrated.

Subjects: Genetics and Genomics

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