Genetics of Age-Related Macular Degeneration

描述(申请人提供)：在美国，有200万人合法失明，还有1000万人因年龄相关性黄斑变性(AMD)而视力受损。在接下来的十年里，这种情况的发生率预计会翻一番。目前，治疗的目标是通过膳食补充剂和激光疗法来限制疾病的进展。与这项研究计划相关的长期目标是更好地了解这种疾病背后的遗传变异，以便识别那些处于疾病风险中的人，为AMD的分子病理生理学提供洞察，并建立预防策略和新的治疗方法。这项特殊的续展申请的目的是继续和推进我们的工作，利用大家庭来识别与AMD发展有关的基因。我们的中心假设仍然是，多个基因参与决定疾病易感性。我们将以我们头五年的调查数据为指导，在这项调查中，涉及100多个大家庭的1000多个人的遗传连锁研究已经确定了几个潜在的易感基因，并将这种名为hemicentin-1的基因与这种疾病的发病机制有关。我们建议通过追求以下具体目标来继续检验这一假设：1)收集额外的受试者并对其进行基因分型，以扩大先前已确定的家系并增加新的大型家系；2)进行统计分析以识别和提炼潜在的疾病基因座，包括a)参数和非参数方法，b)样本分层，以及c)数量性状基因座；以及3)通过a)我们的家系的位置候选基因关联分析，b)我们的病例对照队列的位置候选基因关联分析，以及c)识别上位性交互作用中涉及的基因来寻找和识别AMD易感基因。我们仍然坚信，我们的方法是创新的，因为我们拥有患有这种晚发性疾病的大家庭的独特资源，而且具有重要意义，因为基于迄今收集的数据，这项研究将继续促进对老年性黄斑变性遗传学的理解，老年性黄斑变性是老年人失明的首要原因。

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.