GENETIC EPIDEMIOLOGY OF ALZHEIMER'S DISEASE

阿尔茨海默病的遗传流行病学

• 批准号: 6267266
• 负责人: ROBERT E FERRELL
• 金额: $ 18.9万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-05-15 至 1999-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6267266
• 关键词: African American; Alzheimer's disease; alleles; amyloid proteins; apolipoprotein E; behavioral genetics; caucasian American; disease /disorder proneness /risk; epidemiology; family genetics; gene mutation; genetic markers; genetic polymorphism; genotype; human genetic material tag; human subject; linkage disequilibriums; linkage mapping; nucleic acid sequence; polymerase chain reaction; racial /ethnic difference; restriction fragment length polymorphism

The goal of this study is to systematically examine the impact of genes on risk of occurrence, age-at-onset, severity, and progression of clinical symptoms of Alzheimer's Disease (AD), and the joint effects of epidemiological and genetic risk factors on these same variables in the white and black populations served by the University of Pittsburgh Alzheimer's Disease Research Center (ADRC). Cases will be classified as familial on the basis of having two first degree relatives with probable or confirmed Alzheimer's disease, or as non-familial. Linkage analysis will be used to classify familial cases as involving chromosome 14, 19, 21 or other unidentified loci and association studies with markers tightly linked to chromosome 14q24.3 and apolipoprotein E genotype (chromosome 19) will be used to achieve the following specific aims: 1. In familial cases, to expand the pedigrees of familial cases and perform linkage analysis to identify families segregating for known susceptibility genes, and to identify potential gene carriers within those families to test the following hypotheses: (1): Inherited susceptibility to Alzheimer's disease is completely explained by mutations in chromosome region 14q24.3, the amyloid precursor protein locus (APP) on human chromosome 21 and/or the apolipoprotein E (apoE) locus on human chromosome 19. (2): Familial Alzheimer's disease in African-Americans is explained by mutations in the same genes identified in Caucasians. (3): Clinical characteristics of patients with mutations predisposing to Alzheimer's disease are independent of the specific locus involved. 2. In non-familial cases, to genotype cases and matched controls drawn from the African-American and Caucasian clients of the ADRC for the apolipoprotein E polymorphism, and for markers tightly linked to the Alzheimer's disease locus on chromosome 14q24.3, to test the following hypotheses. (1): The occurrence of Alzheimer's disease associated with genotypes at the apo E locus is independent of ethnic classification. (2): The occurrence of Alzheimer's disease associated with the apo E locus is independent of epidemiological risk factors. (3): The clinical and histopathological characteristics of Alzheimer's disease are independent of apo E genotype. (4): There is no association between risk of Alzheimer's disease and markers linked to the AIzheimer's gene region on chromosome 14q24.3. 3. In cases of autopsy confirmed AD, to sequence the exons and flanking intron-exon boundaries, and the 5'-promoter regions of the apoE gene from cases and controls homozygous for the apoE E3 and E4 alleles to test the following hypothesis: Hypothesis: The association of AD with the apoE locus is determined by DNA sequence variation in linkage disequilibrium with, but independent of, the substitutions responsible for the well know apolipoprotein E polymorphism. While some of these hypotheses have been tested in Caucasian AD families and cases, they have not been tested in African Americans. The latter is a major focus of this proposal.

这项研究的目的是系统地检查基因的影响， 关于临床疾病的发生风险、发病年龄、严重程度和进展 阿尔茨海默病（AD）的症状，以及 流行病学和遗传风险因素对这些相同的变量， 匹兹堡大学服务的白色和黑人人口 阿尔茨海默病研究中心（ADRC）。则标本为 家族的基础上有两个一级亲属与可能 或确诊的阿尔茨海默病或非家族性的连锁分析 将用于将家族性病例分类为涉及染色体14，19， 21或其他未鉴定的位点与标记物紧密关联的研究 与染色体14q24.3和载脂蛋白E基因型（染色体19）连锁 将用于实现以下具体目标：1。在家族案件中， 扩大家族性病例的家系，进行连锁分析， 鉴定分离已知易感基因的家族，以及 在这些家庭中确定潜在的基因携带者， 以下假设：（1）：遗传易感性阿尔茨海默病 完全可以用染色体区域14q24.3的突变来解释， 人21号染色体上的淀粉样前体蛋白基因座（APP）和/或 人19号染色体上的载脂蛋白E（apoE）基因座。(2)：家庭 非裔美国人的阿尔茨海默病可以通过基因突变来解释。 在白种人身上发现了相同的基因(3)：临床特征 易患阿尔茨海默病的突变患者 独立于所涉及的特定位点。2.在非家族性病例中， 基因型病例和匹配的对照组来自非洲裔美国人， ADRC的白种人客户的载脂蛋白E多态性，和 寻找与染色体上的阿尔茨海默病基因座紧密相关的标记 14q24.3，测试以下假设。(1)：发生 阿尔茨海默病与载脂蛋白E基因座基因型相关， 独立于种族分类。(2)老年痴呆症的发生 与载脂蛋白E基因座相关的疾病与流行病学无关， 危险因素(3)：临床和组织病理学特征 阿尔茨海默病与载脂蛋白E基因型无关。(4)：没有 阿尔茨海默病风险与与阿尔茨海默病相关标志物之间的关联 位于染色体14q24.3上的AIIB基因区。3.在尸体解剖的情况下 确认AD，对外显子和侧翼内含子-外显子边界进行测序， 以及来自病例和对照的apoE基因的5 ′-启动子区 apoE E3和E4等位基因纯合子，以检测以下 假设：假设：AD与apoE基因座的关联是 由连锁不平衡的DNA序列变异决定，但 独立的，负责众所周知的替代品 载脂蛋白E多态性虽然其中一些假设已经被 在高加索AD家族和病例中进行了测试，但尚未在 非裔美国人后者是本建议的一个主要重点。