Genetic Variations in Age-related Macular Degeneration

年龄相关性黄斑变性的遗传变异

• 批准号: 7094436
• 负责人: ANAND SWAROOP
• 金额: $ 37.59万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 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/7094436
• 关键词: aging; cholesterol; clinical research; family; genes; genetics; immunoregulation; lipids; macular degeneration; stress

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：年龄相关性黄斑变性（AMD）是65岁以上人群无法治愈的失明的主要原因。目前，大多数AMD患者没有有效的治疗方法。人们普遍认为AMD是一种多因素疾病，涉及遗传和环境因素的相互作用。遗传学研究已经确定了一些染色体位点具有潜在的AMD易感基因。我们和其他人最近发现了与AMD易感性相关的几个基因的遗传变异[如补体因子H (CFH)， toll样受体4 （TLR4）和载脂蛋白E (APOE)]。我们研究的主要目的是剖析AMD发病机制的遗传和分子机制。在本项目中，我们建议检验以下假设：(i)多个易感位点的遗传变异使个体易患AMD发病；（ii）一些易感基因座编码的基因产物与应激反应、脂质和/或胆固醇代谢以及免疫调节有关。具体目的是：(1)收集1500名无血缘关系的AMD先证者及其家庭成员和1000名无血缘关系的年龄（和种族）匹配对照者的详细临床表现、家族史、辅助数据（如吸烟和饮食）和血液/DNA样本；(2)利用广泛的基于单核苷酸多态性（SNP）的关联研究，完善5p、9q、10q和22q染色体上被认为含有AMD易感基因的关键基因组区域，并在我们的队列中确定与晚期AMD相关的遗传变异；(3)在我们的病例对照队列中进行关联研究，使用来自100个候选基因的SNP标记，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)对400-500个AMD相对对的第二个独立样本进行全基因组扫描，以鉴定和验证新的和已建立的AMD易感位点。易感基因（和遗传变异）的鉴定将促进我们对导致AMD发病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会导致AMD的诊断标记物的鉴定，并可能开发新的治疗方法。