Genetic Susceptibility to Age-Related Macular Degeneration

描述(由申请人提供)：年龄相关性黄斑变性(AMD)是一种高度流行的、晚发的复杂疾病，由相互作用的遗传和环境因素共同引起。最近的研究已经确定了几个孟德尔基因座，其中最著名的是编码补体系统蛋白的基因，它们与AMD的发生密切相关。这些基因座目前可以解释50%-70%的疾病，因此其他原因因素肯定参与了疾病的发展。事实上，多条证据表明各种环境因素在AMD中起到了作用。例如，有人提出，饮食、吸烟和光化学损伤会增加氧化应激，从而促进AMD的发展。这些环境因素通过非孟德尔遗传机制发挥作用，包括基因表达的表观遗传调节和线粒体DNA(MtDNA)的损伤，这些都已在各种晚发型复杂性状中得到证实。所有这些发病机制都没有在AMD中得到全面研究。这一建议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的体细胞变异在AMD中起重要作用的假说。为了研究这一假说，我们将利用一个独特的资料库，包括4,000个具有广泛特征(包括临床和遗传学)的人类供体眼睛和先进的遗传分析方法，以解决下列特定目标：1)通过使用先进的图像分析增强AMD病例的表型，完善我们关于AMD内源性表型和基因型/表型相关性的知识；2)确定拷贝数变化与AMD相关的特定基因/位点；3)评估基因表达的表观遗传调控在AMD的发展中的作用；4)评估mtDNA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”原因的发现将有助于提供与疾病病因学有关的重要新信息，并将揭示潜在的新的替代生物标记物和诊断测试。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目标。 与公共健康相关：AMD是导致老年人视力丧失的最常见原因，影响着数百万美国人，这是一个重大的公共健康问题，目前治疗方案有限，具有姑息性。几个主要的孟德尔遗传基因与AMD相关(解释了大约50%的疾病)，然而，对另一半可能由环境因素和非孟德尔因素组成的基因座知之甚少。识别基因的拷贝数变异、其甲基化/表达状态和线粒体DNA的变异以及由此产生的病理生理效应将有助于提供与疾病病因有关的新信息，将揭示潜在的替代生物标志物和诊断试验，并将为这种极其普遍和毁灭性的疾病的治疗提供药理学靶点。

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.