RISK GENES IN ALZHEIMERS DISEASE

阿尔茨海默病的风险基因

• 批准号: 2699799
• 负责人: M. Ilyas Kamboh
• 金额: $ 36.95万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-05-29 至 2001-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2699799
• 关键词: African American; Alzheimer's disease; alleles; caucasian American; chymotrypsin inhibitor; clinical chemistry; clinical research; disease /disorder proneness /risk; enzyme linked immunosorbent assay; epidemiology; gel electrophoresis; gene expression; genetic markers; genetic polymorphism; genotype; human genetic material tag; human subject; image processing; immunocytochemistry; neuritic plaques; nucleic acid sequence; polymerase chain reaction; postmortem; protein signal sequence; racial /ethnic difference; stress proteins

Genetic and functional studies have identified the APOE*4 allele as a strong susceptibility marker for both early- and late-onset Alzheimer's disease (AD). However, the observation that the APOE*4 allele is neither necessary nor sufficient for the expression of AD suggest the possible involvement of additional genetic factors which, either alone or in conjunction with the APOE*4 allele, increase an individual's risk of developing AD. The overall objective of this study is to evaluate the role of genetic variations in other candidate (susceptibility) genes that may alter the risk of AD in the presence or absence of the APOE*4 allele. The chosen candidate genes are involved either in inflammation and the reaction of neuritic plaque or in the cellular pathology of the disease. The objectives of the study will be achieved by fulfilling the following specific aims: 1) to confirm our preliminary observation that a common genetic variation in the signal peptide of ACT is involved in altering the AD risk associated with the APOE*4 allele, 2) to determine ACT levels in plasma and cerebrospinal fluid (CSF) in controls and AD patients and determine the impact of the ACT signal peptide polymorphism in affecting ACT levels ina the two groups. 3) to estimate the extent of neuritic and diffuse plaque formation among the ACT genotypes, 4) in autopsy confirmed AD cases with the ACT/AA genotype, to sequence the exons and flanking intron-exon boundaries of the ACT gene to determine the location of the putative functional mutation, 5) to evaluate the role of known polymorphisms in the c-FOS CTSG, CTSD, UBC, IL1A, IL1B and IL1RN genes and their joint effects with the APOE and ACT polymorphisms in affecting the risk of AD, and 6) to establish new genetic polymorphisms in the HSPA2 and MAPT genes and evaluate their relationships with AD risk alone as well as in combination with APOE, ACT and other polymorphisms as defined in aim 5. The proposed focused genetic and epidemiological studies will enable us to delineate the role of several candidate genes in further refining and defining the role of genes in determining the risk and natural history of AD.

遗传和功能研究已将APOE*4等位基因确定为一个 早期和晚期阿尔茨海默氏症的强敏感标记 疾病（AD）。 但是，观察到apoe*4等位基因都不是 必要或足以表达AD的表明可能 参与其他遗传因素，无论是单独还是在 与apoe*4等位基因共同，增加个人的风险 开发广告。 这项研究的总体目的是评估角色 其他候选者（易感性）基因的遗传变异 在存在或不存在APOE*4等位基因的情况下改变AD的风险。 这 选定的候选基因涉及炎症和反应 神经斑块或疾病的细胞病理学。 这 研究的目标将通过实现以下内容实现 具体目的：1）确认我们的初步观察 ACT信号肽的遗传变异参与改变 与ApoE*4等位基因相关的广告风险，2）确定ACT级别 对照和AD患者的血浆和脑脊液（CSF），以及 确定ACT信号肽多态性在影响影响的影响 行动级别为两组。 3）估计神经和 ACT基因型之间的弥漫斑块形成，4）在尸检中证实 具有ACT/AA基因型的AD病例，以对外显子进行测序 ACT基因的内含子 - 外观边界以确定 假定的功能突变，5）评估已知的作用 C-FOS CTSG，CTSD，UBC，IL1A，IL1B和IL1RN基因的多态性以及 它们与APOE的共同影响并在影响的 AD的风险和6）在HSPA2和 启动基因并评估他们与AD风险的关系以及 结合APOE，ACH和其他多态性，如AIM 5所定义。 拟议的重点遗传学和流行病学研究将使我们能够 描述了几个候选基因在进一步的完善和 定义基因在确定的风险和自然历史中的作用 广告。