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: 7653706
• 负责人: ROBERT PAUL FRIEDLAND
• 金额: $ 107.84万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 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 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7653706
• 关键词: Age; Alleles; Alzheimer' s Disease; Alzheimer' s disease risk; Apolipoprotein E; Arabs; Attention; Base Pairing; Biochemical; Blood Pressure; Blood Vessels; Blood specimen; Candidate Disease Gene; Caucasians; Caucasoid Race; Censuses; China; Chromosomes, Human, Pair 17; Chromosomes, Human, Pair 2; Chromosomes, Human, Pair 9; Communities; Craniocerebral Trauma; DNA; Data; Dementia; Disease; Disease Association; Disease susceptibility; Education; Educational Background; Elderly; Enzyme Gene; Essential Hypertension; Europe; European; Family; Founder Effect; Frequencies; Funding; Gender; Gene Order; Genes; Genetic; Genetic Polymorphism; Genetic Predisposition to Disease; Genome Scan; Genotype; Goals; Haplotypes; High Prevalence; Homocysteine; Homocystine; Hypertension; Inbreeding; Investigation; Israel; Light; Linkage Disequilibrium; Maps; Methods; Occupations; Pathway interactions; Peptidyl-Dipeptidase A; Persons; Pharmaceutical Preparations; Physical Education; Plasma; Population; Predisposition; Prevalence; Process; Psyche structure; Recording of previous events; Relative (related person); Research; Resolution; Risk; Risk Factors; Signal Transduction; Single Nucleotide Polymorphism; Smoking; Surveys; Susceptibility Gene; Time; Vascular Diseases; base; cohort; density; gene therapy; genetic pedigree; genotyping technology; informant; lymphoblastoid cell line; meetings; member; non-genetic; normotensive

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）：我们发现阿尔茨海默病（AD）在以色列北部一个近亲繁殖的阿拉伯社区的患病率非常高（占60岁或以上人群的20%）。这一观察结果显然与APOE c4等位基因无关，APOE c4等位基因在痴呆和非痴呆老年人中的频率<4%。一项低分辨率的基因组扫描和精细的图谱研究揭示了一些染色体区域的阿尔茨海默病易感性位点，这些位点与先前的近亲繁殖的高加索人群的研究有关。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遗传病因的调查中，我们巧合地发现高血压患病率非常高，而高血压与AD有关。