Sibling Study of Age-Related Macular Degeneration

我们研究的总体目标是阐明潜在的机制、途径和生物标记 这可能使个人易患晚期老年性黄斑变性(AMD)，因此适当的 可以开发预防和治疗目标。通常情况下，视网膜的退化已经 从患者在临床上被诊断为AMD时开始。目前的大多数治疗方法都是针对 新生血管性AMD(一种晚期和更严重的疾病)，需要侵入性的分娩方法， 它们的适用性有限，而且不能长期预防或扭转视力损失。 AMD遗传学的重要工作已经确定了1号和10号染色体上的等位基因和单倍型， 特别是在CFH和LOC387715/ARMS2/HTRA1中，因为对AMD风险有很大影响的人群 不同的种族。由于CFH的发现，对补体途径的进一步研究 揭示了AMD风险与C2/CFB、C3和CFH1-5的罕见等位基因之间的关联。尽管这些 研究表明研究整个遗传途径的重要性，而不是孤立地研究一个基因 为AMD等常见疾病开发有效的治疗方法，在世界上有许多人没有AMD 携带这些疾病易感基因/单倍型和大量AMD的人群 在这些基因座上缺乏风险变异的患者。虽然这些发现已经开始为AMD提供洞察力 在病因学上，仍有许多关于AMD风险和发病机制的问题无法用 已知的AMD相关基因和重要的基因座仍有待鉴定和表征。在这 竞争性续签提案，申请者与来自不同学科的领先研究人员合作 (分子遗传学、统计遗传学和蛋白质组学)，旨在进一步识别和评估基因的作用。 使用表型良好的特征和记录的极端同胞对队列的变体。该方法 是多管齐下的，将使用最先进的方法来精确定位与生物相关的疾病目标 以及它们的修饰物，可能使个体容易患上新生血管性AMD。为此，申请者将 初步评估来自与特定候选区域直接相关的高密度SNP/CNV阵列的数据 以及从基因组间获得的基因收敛的初步发现，全基因组范围内 新生血管性AMD风险的关联和基因表达分析。申请者期望得到以下结果 该项目将为更好地了解AMD的发病机制和 从而进一步制定治疗和预防这一疾病的战略。

The overall goal of our research is to elucidate underlying mechanisms, pathways and biological markers which may predispose individuals to advanced age-related macular degeneration (AMD) so that appropriate preventive and therapeutic targets can be developed. Commonly, the degeneration of the retina has already begun by the time the patient is diagnosed with AMD in the clinic. Most current treatments are directed against neovascular AMD (an advanced and more severe form of the disease), require invasive delivery methods, are limited in their applicability, and not capable of preventing or reversing vision loss over the long term. Significant work in AMD genetics has established alleles as well as haplotypes on chromosomes 1 and 10, particularly in CFH and LOC387715/ARMS2/HTRA1, as having large influences on AMD risk in populations of various ethnicities. As a result of the CFH findings, further investigation of the complement pathway has revealed associations between AMD risk and rare alleles in the C2/CFB, C3 and CFH1-5. Although these studies illustrate the importance of studying entire genetic pathways rather than one gene in isolation to develop effective therapies for common diseases such as AMD, there are many AMD free individuals in the population that harbor these disease susceptibility genotypes/haplotypes and a substantial number of AMD patients who lack risk variants in these loci. While these findings have begun to provide insights into AMD etiology, there are still many questions about AMD risk and pathogenesis that cannot be explained by the known AMD-related genes and therefore important loci remain to be identified and characterized. In this competitive renewal proposal, the applicants, working with leading investigators from diverse disciplines (molecular genetics, statistical genetics and proteomics), aim to further identify and evaluate the role of genetic variants using a phenotypically well-characterized and documented cohort of extreme sibpairs. The approach is multi-pronged and will employ state of the art methodologies to pinpoint biologically relevant disease targets and their modifiers that may predispose an individual to neovascular AMD. To this end, the applicants will initially evaluate data from high density SNP/CNV arrays that are directly relevant to specific candidate regions and genes obtained from preliminary findings of genomic convergence between linkage, genome wide association and gene expression analysis on risk of neovascular AMD. The applicants anticipate that results of this project will provide a solid foundation on which to build a better understanding of AMD pathogenesis and thereby furthering the development of strategies for therapy and prevention of this disease.