Genetics of Alzheimer's Disease in Israeli Arabs

以色列阿拉伯人阿尔茨海默病的遗传学

• 批准号: 6918787
• 负责人: ROBERT PAUL FRIEDLAND
• 金额: $ 113.56万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-09-30 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6918787
• 关键词: Alzheimer' s disease; Arabs; cardiovascular disorder risk; clinical research; essential hypertension; family genetics; genetic susceptibility; human genetic material tag; human population genetics; human subject; linkage mapping; single nucleotide polymorphism

DESCRIPTION (provided by applicant): We found a very high prevalence of Alzheimer disease (AD) (20% of those 60 years or older) in an inbred Arab community in northern Israel. This observation is apparently unrelated to the APOE c4 allele which has a frequency of <4% in demented and non-demented elders. A low resolution genome scan and fine mapping studies uncovered AD susceptibility loci in several chromosomal regions that have been implicated in previous studies of outbred Caucasian populations. We also found association between AD and several single nucleotide polymorphisms (SNPs) in the angiotensin converting enzyme gene on chromosome 17. During our investigation of the genetic etiology of AD in this community, we discovered coincidentally a very high prevalence of hypertension which was associated with AD. Going forward, the primary focus of our project remains the genetic basis of AD. In light of emerging evidence for a vascular component to AD risk, we plan to expand the scope of the study to investigate genetic pathways for hypertension, and more specifically, the relationship between the two disorders in this population. To accomplish these goals, we will screen all persons residing in this community ages 65 and older (approximately 2,163) for dementia, and will obtain from a carefully selected subset of 750 cohort members (including 150 subjects meeting AD criteria, 150 subjects with essential hypertension, 150 subjects with both AD and hypertension, and 300 non demented, normotensivc controls) risk factor data and blood samples for biochemical and DNA studies and for establishing lymphoblastoid cell lines. Our scientific aims are: 1) Identify 100,000 base pair regions containing AD (and possibly hypertension) susceptibility genes on chromosomes 9, 10, 12 and 17 by profiling 600 SNPs spanning 15 million base pairs in each of the four previously implicated chromosomal regions using high throughput genotyping technology; and evaluate these data using allelic and haplotype association methods; 2) Fine-map disease loci in the 100 kb regions showing significant association in Aim 1 using a grid of SNPs in 20 kb intervals, and repeating this process iteratively with a higher density of SNPs until the maximum linkage disequilibrium is attained; 3) Evaluate association between disease and 50 genes within the intervals showing the strongest signals in Aim 2 by genotyping additional SNPs and sequencing as necessary; 4) Evaluate association between disease and 100 genes with an emphasis on genes previously implicated in AD and genes involved in vascular functioning; and 5) Determine the relative contributions of SNPs showing significant association to disease susceptibility and investigate interactions among SNPs from multiple loci and with other factors including plasma homocysteine levels and education. The ultimate goal of this study is to find new targets (genetic and non-genetic) for therapy.

描述（由申请人提供）：我们发现在以色列北方的一个近亲繁殖的阿拉伯社区中，阿尔茨海默病（AD）的患病率非常高（60岁或60岁以上的人群中有20%）。这一观察结果显然与APOE c4等位基因无关，该等位基因在痴呆和非痴呆老年人中的频率<4%。一个低分辨率的基因组扫描和精细定位研究发现AD易感基因座在几个染色体区域，已牵连在以前的研究远交高加索人群。我们还发现AD与17号染色体上血管紧张素转换酶基因的几个单核苷酸多态性（SNP）之间存在关联。在我们对该社区AD遗传病因学的调查中，我们意外地发现了与AD相关的高血压患病率非常高。 展望未来，我们项目的主要重点仍然是AD的遗传基础。鉴于血管成分与AD风险的新证据，我们计划扩大研究范围，以调查高血压的遗传途径，更具体地说，这两种疾病之间的关系。为了实现这些目标，我们将对居住在这个社区的所有65岁及以上的人进行筛查。（约2，163）为痴呆症，并将从精心挑选的750名队列成员的子集中获得（包括150例符合AD标准的受试者，150例原发性高血压受试者，150例AD和高血压受试者，300例非痴呆受试者，正常血压对照）的风险因素数据和血液样品，用于生物化学和DNA研究以及用于建立淋巴母细胞系。 我们的科学目标是：1）鉴定含有AD的100，000个碱基对区域通过使用高通量基因分型技术在四个先前涉及的染色体区域中的每一个中分析跨越1500万个碱基对的600个SNP，在染色体9、10、12和17上的（和可能的高血压）易感基因;并使用等位基因和单倍型关联方法评估这些数据; 2）使用20 kb间隔的SNP网格，在100 kb区域中精细绘制显示Aim 1中的显著关联的疾病基因座，并使用更高密度的SNP迭代地重复该过程，直到达到最大连锁不平衡; 3）通过基因分型额外的SNP和必要时测序，评估疾病与在目标2中显示最强信号的区间内的50个基因之间的关联; 4）评估疾病与100个基因之间的关联，重点是先前涉及AD的基因和涉及血管功能的基因;和5）确定显示与疾病易感性显著相关的SNP的相对贡献，并研究来自多个基因座的SNP之间的相互作用以及与其他因素（包括血浆）的相互作用。同型半胱氨酸水平和教育。本研究的最终目标是找到新的治疗靶点（遗传和非遗传）。