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，除了可以应用于一小部分有短期疗效的患者的激光光凝疗法外，还没有可靠的治疗方案可用于AMD。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。这包括：1)完成大量临床和遗传学特征良好的AMD患者和配对对照队列(各2000个样本)；2)利用高通量筛选方法，包括我们实验室最近推出的基因分型微阵列，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(&gt；400万)衍生基因与AMD的特定(内)表型相关联；4)发展动物模型，以进一步确定AMD功能途径中与AMD相关的候选基因，并确定遗传学研究的功能相关性。我们在这一研究领域的进展和经验表明，一个成功的项目应该包括上述所有组成部分。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. 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.