Genetics of Age-Related Macular Degeneration

描述（由申请人提供）：在美国，有200万人是法定失明，还有1000万人患有老年性黄斑变性（AMD）。在未来十年，这种情况的发病率预计将增加一倍。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的进展。与该研究项目相关的长期目标是更好地了解这种疾病的遗传变异，以便识别那些有疾病风险的人，为AMD的分子病理生理学提供见解，并建立预防策略和新的治疗方法。这个特殊的更新申请的目的是继续和进一步我们的工作，以确定参与AMD发展的基因使用大家庭。我们的中心假设仍然是多种基因参与决定疾病的易感性。我们将以前五年的研究数据为指导，其中涉及来自100多个大家庭的1000多名个体的遗传连锁研究已经确定了几个潜在的易感位点，并将基因hemicentin-1与该病的发病机制联系起来。我们建议通过追求以下具体目标来继续测试这一假设：1)收集和基因分型额外的受试者，以扩大先前确定的家庭和增加新的大谱系；2)进行统计分析，以确定和完善潜在的疾病位点，包括a)参数和非参数方法，b)样本分层，c)数量性状位点；3)通过对我们的家系进行位置候选基因关联分析，对我们的病例对照队列进行位置候选基因关联分析，以及对参与上位性相互作用的基因进行鉴定，找到并鉴定AMD的易感基因。我们仍然相信我们的方法是创新的，因为我们拥有独特的迟发性疾病家族资源，并且基于迄今收集的数据，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，黄斑变性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.