Genetics of Age-Related Macular Degeneration

描述（由申请人提供）：在美国，有200万人是法定盲人，还有1000万人因年龄相关性黄斑变性（AMD）而视力受损。在未来十年，这种情况的发生率预计将翻一番。目前，治疗的目的是通过膳食补充剂和激光治疗来限制疾病进展。与该研究计划相关的长期目标是更好地了解疾病背后的遗传变异，以识别疾病风险，深入了解AMD的分子病理生理学，并建立预防策略和新的治疗方法。这个特别的更新申请的目的是继续和进一步我们的工作，以确定基因参与发展的AMD使用扩展的家庭。我们的中心假设仍然是多个基因参与决定疾病易感性。我们将以我们前五年的调查数据为指导，其中涉及来自100多个大家族的1000多个个体的遗传连锁研究已经确定了几个潜在的易感基因座，并涉及基因hemictin-1在该病发病机制中的作用。我们建议通过追求以下具体目标来继续检验该假设：1）收集更多受试者并对其进行基因分型，以扩大之前确定的家族并添加新的大谱系; 2）进行统计分析以识别和细化潜在的疾病位点，包括a）参数和非参数方法，B）样本分层，以及c）数量性状位点;和3）通过a）我们的家系的位置候选基因关联分析，B）我们的病例-对照组的位置候选基因关联分析，和c）涉及上位相互作用的基因的鉴定，发现和鉴定AMD易感基因。我们仍然相信，我们的方法是创新的，因为我们拥有这种迟发性疾病的大家庭的独特资源，并且根据迄今为止收集的数据，这项研究将继续推进对年龄相关性黄斑变性遗传学的理解，这是老年人失明的主要原因。

DESCRIPTION (provided by applicant): In the United States, two million individuals are legally blind and ten million more visually impaired from age-related macular degeneration (AMD). In the next decade, the incidence of this condition is expected to double. Currently, treatment is aimed toward limiting disease progression using dietary supplements and laser therapies. The long range goal associated with this research program is to better understand the genetic variation that underlies the condition in order to identify those at risk of the disease, provide insight into the molecular pathophysiology of AMD and establish prevention strategies and novel treatments. The objective of this particular renewal application is to continue and further our work to identify the genes involved in the development of AMD using extended families. Our central hypothesis remains that multiple genes are involved in determining disease susceptibility. We will be guided by our data from the first five years of investigation in which genetic linkage studies involving over one thousand individuals from more than one hundred extended families have identified several potential susceptibility loci and implicated the gene, hemicentin-1, in the pathogenesis of the condition. We propose to continue to test the hypothesis by pursuing the following specific aims: 1) collect and genotype additional subjects in order to expand previously ascertained families and add new large pedigrees; 2) undertake statistical analyses to identify and refine potential disease loci, to include a) parametric and nonparametric methods, b) sample stratification, and c) quantitative trait locus; and 3) find and identify AMD susceptibility genes by a) positional candidate gene association analyses of our pedigrees, b) positional candidate gene association analysis of our case-control cohorts, and c) identification of genes involved in epistatic interactions. We remain convinced that our approach is innovative because of our unique resource of extended families with this late-onset disease and significant because, based on the data collected to date, this study will continue to advance understanding of the genetics of age-related macular degeneration, the foremost cause of blindness in the elderly.