Genetic Variation in Age-Related Macular Degeneration

描述（由申请人提供）：视网膜相关性黄斑变性（AMD）是60岁以上人群中获得性视力损害的最常见原因。AMD是一种与环境和遗传因素相关的多因素复杂疾病。所有目前可用的治疗方案，即，光动力疗法、激光光凝、抗VEGF化合物是为了暂时缓解一些症状，主要是新血管形成。尽管在过去几年中进行了协调一致的努力，但AMD遗传决定因素的一般知识并没有实质性进展。该提议的基本假设是，个体病例中对AMD的易感性增加是由许多基因中的细微缺陷的组合引起的，即，从特定的基因型。该提案建议继续我们目前的计划，通过几种方法的组合来破译AMD的遗传原因。其中包括：1）完成大的、临床和遗传学上充分表征的AMD患者和严格匹配的对照组群，直到每个达到2000个样本; 2）利用高通量筛选方法，包括我们实验室最近引入的基因分型微阵列，以获得这些人群中遗传异质性的数据; 3）通过统计分析将大量（> 400万）衍生的基因型与AMD中的特定（内）表型相关联。鉴定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，它将使风险个体在发展障碍之前能够准确识别，并有可能改变或预防这种障碍对后代的破坏性视觉后果。

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.