ETIOLOGIC STUDIES OF AGE-RELATED MACULAR DEGENERATION

描述(由申请人提供)：在之前的赠款期间，我们开发了一个广泛的遗传和环境AMD数据库，包括大家庭、具有受影响和未受影响的兄弟姐妹的多重家庭、受影响和不和谐的兄弟姐妹对、受影响的儿童和未受影响的儿童，以及具有良好特征的无关病例和对照。我们还为这些受试者开发了DNA、血清和血浆资料库。我们报告了以下内容：在我们的家族性样本中鉴定了几个遗传连锁区域；在我们的病例对照样本中鉴定了补体因子H(CFH)基因的一个新的变异；确认了CFH和LOC387715/HTRA1基因区域的其他变异；首次确认了BF/C2区域的变异；以及共同的CFH编码多态与环境因素、吸烟和体重指数的独立影响的报告，包括CFH和体重指数之间的相互作用，同时控制了遗传和环境因素，并对AMD遗传学进行了重要回顾。我们还出版了我们的临床年龄相关性黄斑病变分级系统的描述和评估，该系统在过去两个赠款期间一直使用。在下一个资助期内，我们建议在此基础上，使用我们特征良好的研究数据库，目的是寻找与AMD不同阶段的易感性以及疾病进展相关的其他基因，以及遗传变异与生物和环境因素之间的关联。我们将应用大规模的基于家庭的关联研究、基于人群的病例对照关联研究、前瞻性队列分析的方法，以及以已知基因变异为条件的扩展的基于全基因组的家庭连锁研究。为了实现这些目标，我们将完成登记家庭的确定以及病例和对照的招募，完成危险因素数据收集和血液样本获取，并前瞻性地更新兄弟姐妹、儿童和无关受试者的AMD状况，以评估与AMD进展相关的因素。总体目标是将获得的知识转化为与患者管理、预防和更好的治疗相关的有用临床信息，并减少这种流行疾病造成的视力损失。该项目响应NEI的使命，通过解决“AMD的病理生理异质性”和“环境和遗传学在视网膜疾病风险因素中的作用”，将导致更好的“研究疾病进展的基因/表型-环境相关性”，以及“改进的诊断、预防和治疗”。

DESCRIPTION (provided by applicant): During the previous grant periods we developed an extensive genetic and environmental AMD database including large families, multiplex families with affected and unaffected siblings and affected and discordant sib-pairs, affected children and unaffected children, in addition to well-characterized unrelated cases and controls. We also developed a DNA, serum and plasma repository for these subjects. We reported the following: identification of several areas of genetic linkage in our family-based sample; identification of a novel variant in the complement factor H (CFH) gene in our case-control sample; confirmation of other variants in the CFH and LOC387715/HTRA1 gene regions; first confirmation of the variants in the BF/C2 regions; and report of the independent effects of both the common CFH coding polymorphism and environmental factors, smoking and body mass index, including an interaction between CFH and body mass index, while simultaneously controlling for both genetic and environmental factors, and a major review of AMD genetics. We also published the description and evaluation of our Clinical Age-Related Maculopathy Grading System which has been used throughout the last two grant periods. During this next grant period, we propose to build upon this foundation using our well characterized study databases with the goal of finding additional gene or genes associated with susceptibility to various stages of AMD, as well as disease progression, and associations between genetic variants and biologic and environmental factors. We will apply the methodologies of large scale family-based association studies, population-based case-control association studies, prospective cohort analyses, and an expanded genome-wide family-based linkage study conditional on known gene variants for this project. To accomplish these goals, we will complete the ascertainment of enrolled families as well as complete the recruitment of cases and controls, complete risk factor data collection and acquisition of blood specimens, and prospectively update AMD status of siblings, children, and unrelated subjects to assess factors associated with AMD progression. The overall goal is to translate knowledge gained into useful clinical information relevant to patient management, prevention, and better therapies, and to reduce visual loss due to this prevalent disease. This project is responsive to the mission of NEI, by addressing the "pathophysiologic heterogeneity of AMD" and the "roles of the environment and genetics in risk factors for retinal disease" which will lead to better "genotype/phenotype- environment correlations for the study of disease progression" and also "improved diagnosis, prevention, and therapy".