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：
7189837
负责人：
JOHN R HECKENLIVELY
金额：
$ 42.74万
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 2011-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7189837
关键词：
10q 22q Affect Age Age related macular degeneration Alleles Americas Apolipoprotein E Atrophic Biological Blindness Blood CX3CL1 gene Calculi Candidate Disease Gene Cholesterol Cholesterol Homeostasis Choroidal Neovascularization Chromosomes Clinical Compatible Complement Factor H Country Data Databases Development Diagnosis 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 Numbers 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 Week base biological adaptation to stress case control chemokine receptor clinical phenotype cohort cost density design and construction drug discovery fibulin genetic analysis genetic linkage genetic linkage analysis genetic variant genome wide association study genome-wide linkage human CX3CR1 protein immunoregulation improved insight macula novel prevent proband toll-like receptor 4

项目摘要

DESCRIPTION: 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 from 1500 unrelated AMD probands and their family members and 1000 unrelated age- (and ethnically) 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 (and genetic 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.

描述：与年龄相关的黄斑变性（AMD）是65岁以上个体无法治疗失明的主要原因。目前，对于大多数AMD患者，尚无有效的治疗方法。广泛接受的是，AMD是一种涉及遗传和环境因素相互作用的多因素疾病。遗传研究已经确定了许多具有潜在AMD易感基因的染色体基因座。我们和其他人最近鉴定了几种基因（例如补体因子H（CFH），Toll样受体4（TLR4）和载脂蛋白E（APOE）]的遗传变异，它们与AMD的敏感性有关。我们研究的主要目标是剖析基础AMD发病机理的遗传和分子机制。在该项目中，我们建议检验以下假设：（i）多易感性基因座的遗传变异易感性个体对AMD发病机理；（ii）一些敏感性基因座编码参与压力反应，脂质和/或胆固醇代谢以及免疫调节的基因产物。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个无关AMD AMD Probands及其家人的血液/DNA样本以及1000个无关的年龄（和种族）匹配的对照；（2）使用广泛的单核苷酸多态性（SNP）的关联研究并确定我们同胞中与晚期AMD相关的遗传变量，使用大量的单核苷酸多态性（SNP）多态性（SNP）多态性（SNP）多态性（SNP）多态性（SNP）多态性研究，以完善染色体5p，9q，9q，10q和22q的关键基因组区域，这些区域被认为具有AMD易感性基因；（3）使用来自100个选定候选基因的SNP标记在我们的病例对照组中进行关联研究，这些基因编码参与应激反应，脂质 /胆固醇转运和免疫调节的蛋白质；（4）在400-500 AMD相对对的第二个独立样本中执行整个基因组扫描，以识别和验证新颖和已建立的AMD易感基因座。识别易感基因（和遗传变异）将提高我们对有助于AMD发病机理和进展的分子和细胞途径的理解。此外，我们提出的研究可能导致鉴定AMD诊断标记，并可能开发新疗法。