Genetic association of CTNNA3 with late-onset Alzheimer's disease in females
Genetic association of CTNNA3 with late-onset Alzheimer's disease in females
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DOI：
10.1093/hmg/ddm244
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发表时间：
2007-12-01
影响因子：
3.5
通讯作者：
Kuwano, Ryozo
中科院分区：
文献类型：
--
作者：
Miyashita, Akinori;Arai, Hiroyuki;Kuwano, Ryozo
阿尔茨海默病（AD）是老年人中最常见的痴呆形式，通过流行病学研究发现，女性的风险高于男性。因此，我们假设可能存在与性别相关的遗传风险。为了揭示晚发性AD（LOAD）的遗传因素，我们扩展了我们先前在染色体10 q（基因组区域，60-107 Mb）上的遗传工作，并对同一染色体区域进行了基于单核苷酸多态性（SNP）的遗传关联分析，其中在连锁分析中暗示了LOAD中血浆A β 42升高的遗传风险因素的存在。使用总共1408名具有APOE-β 3*3基因型的受试者进行了1140个SNP的两步筛选：我们首先对探索性样本集（LOAD，363;对照，337）进行基因分型，然后对验证样本集（LOAD，336;对照，372）中的一些相关SNP进行基因分型。CTNNA 3内含子9中的7个SNP（约38 kb）在女性中显示与LOAD的多重关联，并且在Mantel-Haenszel检验中显示出更显著的关联（等位基因P值（MH-F）= 0.00005945 -0.0007658）。对2762名受试者（LOAD，1313名;对照，1449名）进行的多元逻辑回归分析表明，7个SNPs中有一个与女性直接相互作用，但与男性不相互作用。此外，我们发现该SNP与APOE-β 4等位基因没有相互作用。我们的数据表明，CTNNA 3可能会影响负载通过女性特异性机制独立的APOE-β 4等位基因。
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 A beta 42 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-epsilon 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-values(MH-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-epsilon 4 allele. Our data suggest that CTNNA3 may affect LOAD through a female-specific mechanism independent of the APOE-epsilon 4 allele.