Genetic Variation in Age-Related Macular Degeneration

描述(申请人提供)：老年性黄斑变性(AMD)是60岁以上人群后天性视力损害的最常见原因。AMD是一种多因素、复杂的疾病，与环境和遗传因素有关。目前所有可用的治疗方案，即光动力疗法、激光光凝、抗血管内皮生长因子化合物，都是针对暂时缓解一些症状，主要是新生血管。尽管在过去的几年里共同努力，但对AMD的遗传决定因素的一般知识并没有实质性的进步。这一建议的基本假设是，在个别病例中，AMD易感性的增加是许多基因的细微缺陷组合的结果，即来自特定的基因(S)。这项建议建议继续我们目前的计划，旨在通过几种方法的组合来破译AMD的遗传原因。这些措施包括：1)完成大量临床和基因特征良好的AMD患者和严格匹配的对照组，直到每个队列达到2000个样本；2)利用高通量筛查方法，包括我们实验室最近推出的基因分型微阵列，以获得这些人群中的遗传异质性数据；3)通过统计分析将大量(&gt；400万)衍生基因与AMD的特定(内向)表型相关联。识别AMD复杂性状的基因、等位基因、单倍型和基因类型，并了解这些缺陷是如何导致黄斑变性的，有可能改善受影响个体的生活质量。此外，它将能够在高危个体发展成疾病之前准确地识别他们，并有可能改变或防止这种疾病在未来几代人中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. All currently available treatment options, i.e., photodynamic therapy, laser photocoagulation, anti-VEGF compounds, are directed towards a temporary relief of some of the symptoms, mainly neovascularization. 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 rigorously matched controls until reaching 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 million) of derived genotypes with specific (endo-)phenotypes in AMD by statistical analyses. 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. Furthermore, 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.