Genetic Susceptibility to Age-Related Macular Degeneration

描述（由申请人提供）：视网膜相关性黄斑变性（AMD）是一种高度流行的迟发性复杂疾病，由相互作用的遗传和环境因素引起。最近的研究已经确定了几个孟德尔基因座，最值得注意的是那些编码补体系统蛋白的基因座，这些基因座与AMD的发展高度相关。这些基因座目前可以解释50-70%的疾病，因此其他因果因素肯定也参与了疾病的发展。事实上，多种证据表明各种环境因素在AMD中的作用。例如，已经提出饮食、吸烟和光化学损伤增加氧化应激，从而促进AMD的发展。这些环境因素通过非孟德尔遗传机制起作用，包括基因表达的表观遗传调节和线粒体DNA（mtDNA）的损伤，这些已在各种晚发型复杂性状中得到证实。这些疾病机制尚未在AMD中进行全面研究。 本研究的主要目的是验证非孟德尔遗传机制如基因拷贝数变异、基因表达的表观遗传调控和线粒体DNA体细胞变异在AMD中发挥重要作用的假说。为了研究这一假设，我们将利用一个独特的知识库，（临床上和遗传学上）人类供体眼睛和遗传分析的先进方法，以解决以下具体目的：1）通过使用先进的图像分析增强AMD病例的表型来完善我们关于AMD内表型和基因型/表型相关性的知识; 2）确定拷贝数变异与AMD相关的特定基因/位点; 3）评估AMD发展中基因表达的表观遗传调控; 4）评估mtDNA中获得性体细胞变异在AMD易感性中的作用。 AMD的其他遗传和“环境”原因的发现将贡献关于疾病病因的重要新信息，并将揭示潜在的新替代生物标志物和诊断测试。更重要的是，拟议的项目可能会为治疗这种极其普遍和毁灭性的疾病提供新的药理学靶点。 公共卫生相关性：AMD是老年人视力丧失的最常见原因，影响了数百万美国人，代表了目前有限的姑息性治疗选择的主要公共卫生问题。已经确定了与AMD相关的几个主要孟德尔遗传位点（解释大约50%的疾病），然而，对可能由环境和非孟德尔成分组成的另一半知之甚少。基因拷贝数变异、其甲基化/表达状态和线粒体DNA变异的鉴定以及由此产生的病理生理效应将提供有关疾病病因的新信息，将揭示潜在的替代生物标志物和诊断测试，并将为治疗提供药理学靶点。这种极其普遍且具有破坏性的疾病。

DESCRIPTION (provided by applicant): Age-related macular degeneration (AMD) is a highly prevalent, late-onset complex disorder caused by a combination of interacting genetic and environmental factors. Recent studies have identified several Mendelian loci, most notably those encoding proteins of the complement system, which are highly associated with the development of AMD. These loci currently explain between 50-70% of the disease, thus other causal factors most certainly participate in the disease development. Indeed, multiple lines of evidence suggest a role for various environmental factors in AMD. It has been proposed, for example, that diet, smoking, and photochemical damage increase oxidative stress, thereby contributing to development of AMD. These environmental factors act through non-Mendelian genetic mechanisms, including epigenetic regulation of gene expression and damage to mitochondrial DNA (mtDNA), which have been documented in various late-onset complex traits. None of these disease mechanisms has been comprehensively studied in AMD. The major goal of this proposal is to test the hypothesis that the non-Mendelian genetic mechanisms such as copy number variation of genes, epigenetic regulation of gene expression and somatic variation in mtDNA play a significant role in AMD. To investigate this hypothesis, we will utilize a unique repository comprised of 4,000 extensively characterized (both clinically and genetically) human donor eyes and advanced methods of genetic analyses to address the following specific aims: 1) refinement of our knowledge relating to AMD endo- phenotypes and genotype/phenotype correlation by enhanced phenotyping of AMD cases using advanced image analysis; 2) determination of specific genes/loci where copy number variation is associated with AMD; 3) assessment of epigenetic regulation of gene expression in the development of AMD and; 4) assessment of the role of acquired, somatic variation in mtDNA in susceptibility to AMD. The discovery of additional genetic and "environmental" causes of AMD will contribute important new information pertaining to disease etiology, and will reveal potential new surrogate biomarkers and diagnostic tests. More importantly, the proposed project will likely provide for new pharmacological targets for the treatment of this extremely prevalent and devastating disorder. PUBLIC HEALTH RELEVANCE: AMD is the most prevalent cause of vision loss in the elderly, affecting millions of Americans representing a major public health problem with currently limited treatment options that are palliative in nature. Several major Mendelian genetic loci associated with AMD (explaining roughly 50% of the disorder) have been identified, however, less is known about the other half possibly consisting of environmental and non-Mendelian components. Identification of copy number variation of genes, their methylation/expression status and variation in mitochondrial DNA and the resulting pathophysiological effects will contribute new information pertaining to disease etiology, will reveal potential surrogate biomarkers and diagnostic tests, and will suggest pharmacological targets for the treatment of this extremely prevalent and devastating disorder.