GENETIC EPIDEMIOLOGY OF ALZHEIMER'S DISEASE

阿尔茨海默病的遗传流行病学

• 批准号: 6295340
• 负责人: ROBERT E FERRELL
• 金额: $ 18.86万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-05-04 至 2000-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6295340
• 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.

本研究的目的是系统地研究基因的影响 发生风险、发病年龄、严重程度和临床进展 阿尔茨海默病 (AD) 的症状以及联合影响 流行病学和遗传风险因素对这些相同变量的影响 匹兹堡大学服务的白人和黑人群体 阿尔茨海默病研究中心（ADRC）。案件将被分类为 家族性的基础是有两个可能的一级亲属 或确诊阿尔茨海默氏病，或非家族性疾病。连锁分析 将用于将家族病例分类为涉及染色体 14、19、 21个或其他未识别位点与标记紧密关联研究 与染色体 14q24.3 和载脂蛋白 E 基因型（19 号染色体）相关 将用于实现以下具体目标： 1. 在家族病例中， 扩大家族病例谱系并进行关联分析 识别因已知易感基因而分离的家庭，并 确定这些家族中潜在的基因携带者以测试 以下假设：(1)：阿尔茨海默病的遗传易感性 完全可以通过染色体区域 14q24.3 的突变来解释， 人类 21 号染色体上的淀粉样蛋白前体蛋白基因座 (APP) 和/或 人类 19 号染色体上的载脂蛋白 E (apoE) 位点。(2)：家族性 非裔美国人的阿尔茨海默病是由基因突变解释的 在白种人中发现了相同的基因。 (3)：临床特征 携带易患阿尔茨海默氏病的突变的患者 独立于所涉及的特定位点。 2. 对于非家族性病例， 基因型病例和匹配的对照来自非洲裔美国人和 ADRC 的白人客户载脂蛋白 E 多态性，以及 与染色体上阿尔茨海默病基因座紧密连锁的标记 14q24.3，检验以下假设。 (1)：发生 阿尔茨海默病与 apo E 位点基因型相关 独立于种族分类。 (2)：阿兹海默症的发生 与 apo E 位点相关的疾病与流行病学无关 风险因素。 (3)：临床和组织病理学特征 阿尔茨海默病与 apo E 基因型无关。 (4)：没有 阿尔茨海默病风险与相关标记物之间的关联 艾茨海默氏症基因区域位于染色体 14q24.3。 3. 尸检时 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' 启动子区域 apoE E3 和 E4 等位基因纯合，以测试以下内容 假设： 假设：AD 与 apoE 基因座的关联是 由连锁不平衡中的 DNA 序列变异决定，但是 独立于众所周知的替换 载脂蛋白E多态性。虽然其中一些假设已被 在白种人 AD 家庭和病例中进行过测试，但尚未在 非裔美国人。后者是本提案的重点。