GENETIC EPIDEMIOLOGY OF ALZHEIMER'S DISEASE

阿尔茨海默病的遗传流行病学

• 批准号: 6295348
• 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: 1998-08-01 至 1999-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6295348
• 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.

这项研究的目标是系统地研究基因的影响。 论临床发病风险、发病年龄、严重程度和进展 阿尔茨海默病(AD)的症状，以及 流行病学和遗传危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人口 阿尔茨海默病研究中心(ADRC)。案件将被归类为 在有两个一级亲属的基础上有可能 或确诊为阿尔茨海默病，或为非家族性。连锁分析 将被用来将家族性病例分类为涉及14，19， 21个或其他未知基因座与标记的紧密关联研究 与染色体14q24.3和载脂蛋白E基因连锁(19号染色体) 将用于实现以下具体目标：1.在家族性病例中， 扩大家族性病例家系并进行连锁分析 确定分离已知易感基因的家系，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 完全可以由染色体14q24.3区域的突变来解释， 人类21号染色体的淀粉样前体蛋白基因座(APP)和/或 人类19号染色体载脂蛋白E(ApoE)基因座(2)：家族性 非裔美国人阿尔茨海默病的原因是基因突变 在高加索人中发现了相同的基因。(3)：本病临床特点 携带易患阿尔茨海默病基因突变的患者 与所涉及的特定基因座无关。2.在非家族性个案中， 来自非裔美国人和非裔美国人的基因型病例和匹配对照 ADRC的高加索客户的载脂蛋白E多态，以及 寻找与染色体上的阿尔茨海默病基因紧密连锁的标记 14q24.3，以检验以下假设。(1)：发生 与载脂蛋白E基因座基因相关的阿尔茨海默病 独立于种族分类。(2)：阿尔茨海默氏症的发生 与载脂蛋白E基因座相关的疾病与流行病学无关 风险因素。(3)临床及组织病理学特点 阿尔茨海默病与载脂蛋白E基因无关。(4)：没有 阿尔茨海默病的风险与与 染色体14q24.3上的AIzheimer‘s基因区。3.在进行身体剖验时 确认AD，对外显子和两侧内含子-外显子边界进行测序， 以及病例和对照的载脂蛋白E基因5‘-启动子区域 对apoE E3和E4等位基因进行纯合以检测以下各项 假设：假设：阿尔茨海默病与载脂蛋白E基因座的关联是 由与连锁不平衡的DNA序列变异决定，但 与之无关的是，这些替换是众所周知的 载脂蛋白E基因多态性。虽然这些假设中的一些已经 在高加索AD家庭和病例中进行测试，它们还没有在 非裔美国人。后者是这项提议的一个主要重点。