Mitochondrial DNA Variations and Susceptibility to Oxidative Injury in the RPE

描述(由申请人提供)：我们最近的研究发现了一种与年龄相关性黄斑变性(AMD)相关的新的遗传变异。在调整了补体因子H、10q26上的LOC387715基因、年龄、性别和吸烟等已知危险因素后，线粒体DNA(MtDNA)4917G等位基因与AMD独立相关(OR=3.30，95%CI 1.25~7.17，p=0.01)。4917G多态是T单倍群线粒体的一种常见变异，导致复合体I的ND2亚单位天冬氨酸天冬氨酸的非同源改变，线粒体在控制细胞能量产生、细胞凋亡和氧化还原动态平衡方面发挥着重要作用。线粒体基因组的突变和多态往往会导致高能量需求组织的病理损伤，如视网膜。视网膜色素上皮(RPE)是AMD的主要病变部位。越来越多的证据表明，氧化应激所致的RPE功能障碍参与了AMD的发生发展。我们假设线粒体基因组中的特定多态控制着RPE中氧化损伤的易感性。这一假设将在以下两个特定目标上进行验证，使用培养的人胎儿RPE细胞，这些细胞不会对随年龄增长而出现的线粒体DNA造成体细胞损伤。具体目的1将确定特定的线粒体DNA多态是否与培养的胎儿RPE细胞对氧化剂诱导的细胞凋亡的敏感性增加有关，以及这种敏感性是否与线粒体遗传变异有关。具体目标2将确定线粒体基因组的变异是否会影响对诱导RPE中抗氧化反应的试剂的反应。这些研究的结果将支持使用mtDNA单倍型作为遗传生物标记物来识别AMD风险增加的人，并可能导致预测补充抗氧化剂或其他增强视网膜抗氧化防御的临床治疗结果的指标。 公共卫生相关性：老年性黄斑变性(AMD)是导致老年人失明的主要原因。最近的研究发现，AMD的发病风险与线粒体基因组中的一种新的遗传变异有关。确定这种变化的功能后果将是当前提案的重点。

DESCRIPTION (provided by applicant): Our recent studies have identified a novel genetic variation associated with age-related macular degeneration (AMD). The 4917G allele of mitochondrial DNA (mtDNA) was independently associated with AMD (OR=3.30, 95% CI 1.25 - 7.17, p=0.01) following adjustment for known risk factors including complement factor H, LOC387715 gene on chromosome 10q26, age, gender and smoking status. The 4917G polymorphism is a common variation in haplogroup T mitochondria and results in a non-synonomous change, asparagine for aspartic acid, in the ND2 subunit of Complex I. Mitochondria play essential roles in controlling cellular energy production, apoptosis and redox homeostasis. Mutations and polymorphisms of the mitochondrial genome often lead to pathological lesions in tissues with high energy demand, such as the retina. The retinal pigment epithelium (RPE) is a primary site of lesion in AMD. Accumulating evidence indicates that oxidative stress induced dysfunction of the RPE contributes to the development and progression of AMD. We hypothesize that specific polymorphisms in the mitochondrial genome control susceptibility to oxidative injury in the RPE. The hypothesis will be tested in the following two specific aims using cultured human fetal RPE cells which do not carry somatic damage to the mtDNA seen with aging. Specific Aim 1 will determine whether specific mitochondrial DNA polymorphisms are associated with increased susceptibility to oxidant-induced apoptosis in cultured fetal RPE cells and whether the sensitivity is associated with mitochondrial genetic variations. Specific Aim 2 will determine whether variations in the mitochondrial genome affect responses to agents that induce the antioxidant responses in the RPE. Results from these studies will support the use of mtDNA haplotypes as a genetic biomarker in identifying people with increased risk of AMD and may lead to predictors of the outcome of clinical treatment with antioxidant supplementation or other agents that augment the antioxidant defense of the retina. PUBLIC HEALTH RELEVANCE: Age-related macular degeneration (AMD) is the leading cause of blindness in elderly people. Recent studies have identified that the risk of developing AMD is associated with a novel genetic variation in the mitochondrial genome. Characterization of the functional consequences of such variation will be the focus of the current proposal.