Genetic Variations in Age-related Macular Degeneration

描述：年龄相关性黄斑变性(AMD)是65岁以上无法治愈的失明的主要原因。目前，大多数AMD患者还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含有潜在AMD易感基因的染色体位点。我们和其他人最近发现了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)]，这些基因与AMD的易感性有关。本研究的主要目的是剖析老年性黄斑变性发病的遗传学和分子机制(S)。在这个项目中，我们建议检验以下假设：(I)多个易感基因座的遗传变异使个体容易发生AMD；以及(Ii)一些易感基因座编码与应激反应、脂肪和/或胆固醇代谢以及免疫调节有关的基因产物。具体目标是：(1)收集1500名无关的AMD先证者及其家庭成员和1000名年龄(和种族)匹配的对照组的详细临床表现、家族史、辅助资料(如吸烟和饮食)和血液/DNA样本；(2)利用广泛的单核苷酸多态性(SNP)关联研究，提炼染色体5p、9q、10q和22q上被认为含有AMD易感基因的关键基因组区域，并鉴定与我们队列中的晚期AMD相关的遗传变异；(3)使用100个候选基因中的SNP标记在我们的病例对照队列中进行关联研究，这些候选基因编码与应激反应、脂质/胆固醇运输和免疫调节相关的蛋白；以及(4)在第二个独立的400-500个AMD亲属对样本中进行全基因组扫描，以识别和验证新的和已建立的AMD易感基因座。识别易感基因(和遗传变异)将促进我们对AMD发病机制和进展的分子和细胞途径的理解。此外，我们建议的研究可能导致识别AMD的诊断标记物，并可能开发新的治疗方法。

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.