Genetic Variation in Age-Related Macular Degeneration

描述（由申请人提供）：年龄相关性黄斑变性（AMD）是60岁以上人群获得性视力障碍的最常见原因。AMD是一种多因素的复杂疾病，与环境和遗传因素有关。目前，除了激光光凝治疗外，没有可靠的治疗方案可用于AMD，该治疗方案可用于一小部分具有短期效果的患者。尽管在过去几年中共同努力，AMD的遗传决定因素的一般知识并没有实质性进展。这一提议的潜在假设是，个体对AMD的易感性增加是由于许多基因中微妙缺陷的组合，即来自特定基因型。该建议建议继续我们目前的计划，旨在通过几种方法的结合来破译AMD的遗传原因。这些包括：1)完成大型，临床和遗传特征良好的AMD患者和匹配对照组队列（各2000个样本）；2)利用高通量筛选方法，包括最近在我们实验室引入的基因分型微阵列，获得这些群体的遗传异质性数据；3)通过统计分析，将大量（约400万）衍生基因型与AMD的特异性（endo-）表型相关联；4)建立动物模型，进一步确定功能通路中amd相关候选基因，并确定遗传研究的功能相关性。我们在这个研究领域的进展和经验表明，一个成功的项目应该包括上面列出的所有组成部分。识别AMD复杂性状的基因、等位基因、单倍型和基因型，并了解这些缺陷如何促进黄斑变性的发展，有可能改善受影响个体的生活质量。此外，它将能够在患病之前准确地识别出有风险的个体，并有可能改变或预防这种疾病对后代造成的破坏性视觉后果。

DESCRIPTION (provided by applicant): Age-related macular degeneration (AMD) is the most common cause of acquired visual impairment in people over the age 60. AMD is a multifactorial, complex disorder associated both with environmental and genetic factors. Currently, no reliable treatment options are available for AMD with the exception of the laser photocoagulation therapy that can be applied to a small fraction of patients with short-term effects. Despite concerted efforts over the last several years, the general knowledge of genetic determinants of AMD has not advanced substantially. The underlying hypothesis of this proposal is that increased susceptibility to AMD in individual cases results from a combination of subtle defects in many genes, i.e., from specific genotype(s). This proposal suggests a continuation of our current program directed towards deciphering the genetic cause of AMD by a combination of several approaches. These include: 1) Completing large, clinically and genetically well-characterized, cohorts of AMD patients and matched controls ((2000 samples each); 2) Utilizing high-throughput screening methods, including recently introduced in our laboratory genotyping microarrays, to obtain data on genetic heterogeneity in these populations; 3) Correlating the large numbers (>4 millions) of derived genotypes with specific (endo-) phenotypes in AMD by statistical analyses; 4) Developing animal models to further define AMD-associated candidate genes in functional pathways and to determine the functional relevance of genetic studies. Our progress and experience in this field of research suggests that a successful project should include all the components listed above. Identification of genes, alleles, haplotypes, and genotypes underlying the AMD complex trait and understanding how these defects contribute to the development of macular degeneration has the potential to improve the quality of life of the affected individuals. Further, it will enable the accurate identification of at-risk individuals before they develop the disorder, and has the potential to modify or prevent the devastating visual consequences of this disorder in future generations.