Genetic Variations in Age-related Macular Degeneration

年龄相关性黄斑变性的遗传变异

基本信息

批准号：
7777286
负责人：
JOHN R HECKENLIVELY
金额：
$ 45.42万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-03-01 至 2011-08-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7777286
关键词：
10q 22q Affect Age Age related macular degeneration Alleles Americas Apolipoprotein E Biological Blindness Blood CX3CL1 gene Calculi Candidate Disease Gene Cholesterol Cholesterol Homeostasis Choroidal Neovascularization Chromosomes Clinical Complement Factor H Country Data Databases Development Diagnostic Diet Disease Elderly Environmental Risk Factor Epidemiologic Studies Family history of Family member Fundus Gene Family Genes Genetic Genetic Predisposition to Disease Genetic Variation Genomics Genotype Goals Haplotypes Human Genetics Individual Inherited Investigation Laboratories Lead Link Lipids Macular degeneration Maps Methods Molecular Molecular Genetics Molecular Target National Eye Institute Nuclear Family Nutritional status Pathogenesis Pathology Pathway interactions Patients Population Predisposition Proteins Race Recruitment Activity Relative (related person)Reporting Research Retina Risk Risk Factors Role Sampling Single Nucleotide Polymorphism Smoking Staging Subgroup Susceptibility Gene Testing Therapeutic Intervention UV Radiation Exposure United States Update Variant Vascular Diseases Visual impairment base biological adaptation to stress case control chemokine receptor clinical phenotype cohort cost density design and construction disease diagnosis drug discovery effective therapy fibulin genetic analysis genetic linkage genetic linkage analysis genetic variant genome wide association study genome-wide linkage geographic atrophy immunoregulation improved insight macula novel prevent proband toll-like receptor 4

项目摘要

Age Related Macular Degeneration (AMD) is the leading cause of untreatable blindness in individuals over the age of 65. Currently, there is no effective treatment available for most patients with AMD. It is widely accepted that AMD is a multi-factorial disease involving the interaction of genetic and environmental factors. Genetic studies have identified a number of chromosomal loci that harbor potential AMD susceptibility genes. We and others have recently identified genetic variants in several genes [such as complement factor H (CFH), toll-like receptor 4 (TLR4) and apolipoprotein E (APOE)] that have been associated with susceptibility to AMD. The primary goals of our research are to dissect genetic and molecular mechanism(s) underlying AMD pathogenesis. In this project, we propose to test the following hypotheses: (i) genetic variations in multiple susceptibility loci predispose individuals to AMD pathogenesis; and (ii) some of the susceptibility loci encode gene products that are involved in stress response, lipid and/or cholesterol metabolism, and immune-modulation. The specific aims are:(1) to collect detailed clinical findings, family history, ancillary data (such as, smoking and diet), and blood/DNA samples from1500 unrelated AMD probands and their family members and 1000unrelated age-(andethnically) matched controls; (2) to refine the critical genomic regions on chromosomes 5p, 9q, 10q and 22q,which are suggested to harbor AMD susceptibility genes, using extensive single nucleotide polymorphism (SNP)-based association studies and to identify the genetic variations that are associated with late-stage AMD in our cohort; (3) to perform association studies in our cohort of case-controls using SNP markers from 100 selected candidate genes that encode proteins involved in stress response, lipid /cholesterol transport, and immune-modulation; and (4) to perform whole genome scan in a second independent sample of 400-500 AMD relative-pairs to identify and validate novel and established AMD susceptibility loci. Identification of susceptibility genes (andgenetic variants) will advance our understanding of molecular and cellular pathways that contribute to the pathogenesis and progression of AMD. In addition, our proposed studies may lead to identification of diagnostic markers for AMD and possibly development of new therapies.

与年龄相关的黄斑变性（AMD）是个体无法治疗失明的主要原因超过65岁。目前，对于大多数AMD患者，尚无有效的治疗方法。这是广泛认为AMD是一种多因素疾病，涉及遗传和环境的相互作用因素。遗传研究已经确定了许多具有潜在AMD的染色体基因座敏感基因。我们和其他人最近鉴定了几种基因的遗传变异[例如补体因子H（CFH），Toll样受体4（TLR4）和载脂蛋白E（APOE）] 与对AMD的敏感性有关。我们研究的主要目标是剖析遗传和分子机制（S）基础AMD发病机理。在这个项目中，我们建议测试以下假设：（i）多种易感基因座的遗传变异倾向于AMD发病机理；（ii）一些易感基因座编码与压力反应，脂质和/或胆固醇代谢和免疫调节。具体目的是：（1）收集详细的临床发现，家族史，辅助数据（例如，吸烟和饮食）以及1500的血液/DNA样本无关的AMD Probands及其家人和1000个无关的年龄（Andethnne）匹配控件；（2）完善染色体5p，9q，10q和22q的关键基因组区域，建议使用广泛的单核苷酸多态性（SNP）携带AMD易感基因关联研究并确定与我们的后期AMD相关的遗传变异队列；（3）使用100个SNP标记在我们的病例对照组中进行关联研究选定的候选基因，这些基因编码涉及压力反应，脂质 /胆固醇转运的蛋白质和免疫调节；（4）在400-500的第二个独立样本中执行整个基因组扫描 AMD相对对识别和验证新颖和建立的AMD敏感性基因座。识别敏感性基因（和属变体）将提高我们对有助于AMD的发病机理和进展的分子和细胞途径。此外，我们提出的研究可能导致鉴定AMD的诊断标记，并可能开发新疗法。