Gene-Environment Interactions in Glaucoma

原发性开角型青光眼(POAG)是慢性视神经病变的主要原因，也是 全球范围内的眼部发病率。了解临床前事件、早期疾病和疾病异质性 代表POAG的早期疾病发现、预防和治疗的主要目标。在这项研究中，我们 提出4个具体目标。1)我们将进行靶向和非靶向代谢组范围的关联 使用大型病例对照组(500例和500例)临床前血清进行的POAG研究 对照)嵌套在正在进行的护士健康研究(NHS)、NHS2和健康前瞻性研究中 专业人员跟踪研究(HPFS)以促进我们对之前的生化事件的了解 POAG诊断(在疾病诊断前约10年采集血液)。先前的研究表明，硝酸盐 氧化代谢物代表遗传信息标记，并将形成靶向分析的基础。2)当 POAG基因已经有了相当大的发现，还需要更多的工作来利用全基因组 告知POAG病因学的信息。因此，我们将创建一个全基因组的遗传相关矩阵 POAG和以前与POAG相关的复杂特征，使用来自邻居(国家眼)的数据 青光眼研究所人类遗传学协作可遗传整体操作数据库；3800 POAG 病例)联盟和可公开获得的全基因组关联研究数据摘要。对美国政府的评估 POAG与这些性状之间的共同遗传力以及遗传风险分数与 这些特征和POAG将导致新的病因学见解。3)新发的POAG在临床上是异质性的 可反映不同病因的可变视野(VF)丢失模式。我们将应用原型分析， 它客观地将患者的VF丢失模式量化为16个现有的临床验证原型(AT)，其中9个 在本质上是青光眼。每个POAG病例(NHS、NHS2和HPFS中的n=1250例)和10例匹配 将为控件分配16个加权系数，每个系数的总和为1，每个值表示 他/她的室颤丢失模式与每个青光眼患者一致。我们将评估微分关系 在已建立的POAG风险因素和16个AT上的值之间，确定独特的风险因素 同类事件POAG子类型。4)限制碳水化合物的饮食可以满足人体的能量需求 无髓鞘视网膜神经节细胞轴突节段的视神经和降低POAG的风险。我们会 根据3个队列中的POAG和POAG亚型对这种暴露进行前瞻性评估 (n=2100例)。通过将MWAS、基因组学与预期的环境暴露数据和AT相结合 分析，这项建议解决了一些重要的知识差距--特别是它将阐明 遗传和诊断前风险因素如何影响POAG和POAG的异质性。链接特定 暴露于POAG亚型将提供重要的机制理解以及证据 因果关系，这将有助于发现针对这种情况的精确医学方法。

Primary open-angle glaucoma (POAG) is the leading cause of chronic optic neuropathy and a major source of ocular morbidity worldwide. Understanding preclinical events, early phase disease and disease heterogeneity represent key objectives in early disease detection, prevention and treatment of POAG. In this study, we propose 4 specific aims. 1) We will perform both targeted and untargeted metabolome-wide association studies (MWAS) for POAG using pre-clinical serum from a large case-control group (500 cases and 500 controls) nested within ongoing prospective studies of the Nurses' Health Study (NHS), NHS2, and Health Professionals Follow-up Study (HPFS) to advance our understanding of the biochemical events that precede POAG diagnosis (blood was collected ~ 10 years prior to disease diagnosis). Prior studies suggest that nitric oxide metabolites represent genetically informed markers and will form the basis for targeted profiling. 2) While considerable discoveries have been made of POAG genes, more work is needed to leverage genome-wide information to inform POAG etiology. Thus, we will create a genome-wide genetic correlation matrix between POAG and complex traits previously linked to POAG, using data from the NEIGHBORHOOD (National Eye Institute Glaucoma Human Genetics Collaboration Heritable Overall Operational Database; 3800 POAG cases) consortium and publicly available summary genome-wide association study data. An assessment of the shared heritability between POAG and these traits as well as the relation between the genetic risk scores for these traits and POAG will lead to new etiologic insights. 3) New-onset POAG is clinically heterogeneous with variable visual field (VF) loss patterns that may reflect different etiologies. We will apply archetype analysis, which objectively quantifies a patient's VF loss pattern to 16 existing clinically validated archetypes (ATs), 9 of which are glaucomatous in nature. Each POAG case (n=1250 from NHS, NHS2 and HPFS) and10 matched controls will be assigned 16 weighted coefficients that add up to 1, with each value representing how consistent his / her VF loss pattern is with each glaucomatous AT. We will evaluate the differential relation between established POAG risk factors and the values on the 16 ATs, to identify unique risk factors for homogeneous incident POAG subtypes. 4) A carbohydrate-restricted diet may meet the energy requirement in the non-myelinated retinal ganglion cell axon segment of the optic nerve and reduce risk of POAG. We will conduct a prospective evaluation of this exposure in relation to POAG and POAG subtypes in the 3 cohorts (n=2100 cases). By integrating MWAS, genomics with prospective environmental exposure data and AT analysis, this proposal addresses a number of important knowledge gaps—in particular, it will shed light on how genetic and pre-diagnostic risk factors influence POAG and POAG heterogeneity. Linking specific exposures with POAG subtypes will provide important mechanistic understanding as well as evidence of causality, which will contribute to discovering precision medicine approaches for this condition.