Genetics of Alzheimer's Disease in Israeli Arabs

描述(由申请人提供)：我们发现在以色列北部的一个近亲繁殖的阿拉伯社区，阿尔茨海默病(AD)的患病率非常高(60岁或以上的人中有20%)。这一观察结果显然与APOE c4等位基因无关，该等位基因在痴呆症和非痴呆症老年人中的频率为4%。低分辨率的基因组扫描和精细的作图研究发现了几个染色体区域的AD易感基因，这些区域在以前的高加索近交群体研究中被牵连。我们还发现了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(SNPs)的关联。在我们对AD的遗传病因学的研究中，我们巧合地发现了与AD相关的高血压的高患病率。 展望未来，我们项目的主要焦点仍然是阿尔茨海默病的遗传基础。鉴于新出现的证据表明血管成分与AD风险有关，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，研究这两种疾病在这一人群中的关系。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(约2,163人)进行痴呆症筛查，并将从精心挑选的750名队列成员(包括150名符合AD标准的受试者、150名原发性高血压受试者、150名同时患有AD和高血压的受试者以及300名非痴呆、血压正常的对照组)中获得危险因素数据和血液样本，用于生化和DNA研究以及建立淋巴母细胞系。 我们的科学目标是：1)通过使用高通量基因分型技术，在先前涉及的四个染色体区域中的每一个区域中的600个跨越1500万个碱基对的SNP中，识别包含9、10、12和17号染色体上的AD(以及可能的高血压)易感基因的100,000个碱基对区域；并使用等位基因和单倍型关联方法对这些数据进行评估；2)使用以20 kb为间隔的SNPs网格，对目标1中显示显著关联的100kb区域的疾病基因座进行精细定位，并以更高密度的SNPs反复重复这一过程，直到达到最大连锁不平衡为止；3)通过对目标2中信号最强的50个基因进行基因分型和必要的测序，评估疾病与50个基因之间的关联；4)评估疾病与100个基因之间的关联，重点是先前与AD有关的基因和涉及血管功能的基因；以及5)确定与疾病易感性显著相关的SNPs的相对贡献，并调查来自多个基因座的SNPs之间以及与其他因素(包括血浆同型半胱氨酸水平和教育程度)之间的交互作用。这项研究的最终目标是找到新的治疗靶点(遗传和非遗传)。

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.