ETIOLOGIC STUDIES OF AGE-RELATED MACULAR DEGENERATION

描述（由申请人提供）：在之前的资助期间，我们开发了一个广泛的遗传和环境AMD数据库，包括大家庭、有患病和未患病兄弟姐妹、患病和不一致兄弟姐妹的多重家庭、患病儿童和未患病儿童，以及特征明确的不相关病例和对照。我们还为这些受试者建立了DNA、血清和血浆库。我们报告了以下内容：在我们以家庭为基础的样本中确定了几个遗传连锁区域；在我们的病例对照样本中发现补体因子H （CFH）基因的新变异；CFH和LOC387715/HTRA1基因区域的其他变异的确认；首先确认BF/C2区域的变体；并报道了常见CFH编码多态性与环境因素、吸烟和体重指数的独立影响，包括CFH和体重指数之间的相互作用，同时控制遗传和环境因素，以及AMD遗传学的主要综述。我们还发表了我们的临床年龄相关黄斑病变分级系统的描述和评估，该系统已在过去两个拨款期间使用。在下一个资助期内，我们建议在此基础上使用我们的特征研究数据库，目标是寻找与AMD不同阶段易感性相关的其他基因或基因，以及疾病进展，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、前瞻性队列分析和基于已知基因变异的扩展全基因组的基于家庭的连锁研究的方法。为了实现这些目标，我们将完成入组家庭的确定以及病例和对照的招募，完成风险因素数据收集和血液标本采集，并前瞻性地更新兄弟姐妹、儿童和非相关受试者的AMD状态，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，并减少由于这种流行疾病造成的视力丧失。该项目响应了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危险因素中的作用”，这将导致更好的“基因型/表型-环境相关性研究疾病进展”，并“改进诊断、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".