Genetic and Environmental Risk Factors for Exfoliation Syndrome and Glaucoma

剥脱综合征(XFS)是一种常见的全身性疾病，其特征是进行性积累 纤维蛋白聚集异常并与青光眼、早熟白内障相关 白内障的形成、白内障手术中的并发症以及几种全身情况。我们的目标是 阐明剥脱综合征(XFS)和相关的青光眼(XFG)的发病机制，这将 促进有效的筛查和预防战略以及新疗法的开发。聚合 LOXL1是致病纤维聚集体的组成部分之一，LOXL1是致病的主要遗传危险因素。 XFS/XFG，LOXL1风险变异出现在高达98%的患者中。然而，XFS/XFG是遗传的 这些相同的常见风险变异也存在于许多未受影响的个体中，这表明 额外的遗传和/或环境因素对于疾病的发展是必要的。在上一次 资助期我们在确定影响XFS/XFG风险的环境暴露方面取得了重大进展 包括户外活动时间、居住纬度、紫外线暴露量、大量饮用咖啡和低叶酸 入口处。与我们的国际联盟合作，我们已经确定了影响风险的新的遗传因素 包括保护性的LOXL1变种。我们还完成了一项代谢组学研究，使用诊断前 纵向护士健康研究(NHS)和卫生专业人员跟踪研究(HPFS)样本 鉴定出两类血浆代谢物(溶血磷脂酰胆碱和磷脂酰乙醇胺 血浆原)，在疾病发生前十年测量，与XFS/XFG增加相关 风险，而个体代谢物可的松和类固醇和甘油三酯的代谢物类别相反 与风险相关。在下一个资助期，我们将在这些结果的基础上使用NHS，NHS2的数据 和HPFS、海量眼耳临床病例对照集合和UK Biobank，以进一步定义复杂的 导致这一重要致盲疾病的风险因素。我们提出了以下具体目标：1) 调查类固醇、脂代谢产物、环境因素与XFS/XFG风险的关系；2) 调查罕见/低频LOXL1变异对XFS/XFG风险的贡献，并3)评估综合 代谢和基因组对XFS/XFG风险的影响。这项独一无二的研究具有全面的前瞻性 环境、遗传和新陈代谢数据和一个多学科团队(遗传学专业知识， 代谢组学、流行病学)将以符合成本效益的方式解决导致眼部疾病的一个重要原因。调查结果 将与临床和公共卫生实践直接相关。

Exfoliation syndrome (XFS) is a common systemic disorder characterized by progressive accumulation of abnormal fibrillar protein aggregates and that is associated with glaucoma (XFG), pre-mature cataract formation, and complications during cataract surgery as well as several systemic conditions. Our goal is to elucidate the pathogenesis of exfoliation syndrome (XFS) and the associated glaucoma (XFG), which will facilitate effective screening and prevention strategies and the development of novel therapies. Aggregated LOXL1 is one component of the pathogenic fibrillar aggregates, and LOXL1 is a major genetic risk factor for XFS/XFG, with LOXL1 risk variants occurring in up to 98% of patients. However, XFS/XFG is genetically complex, and these same common risk variants are also present in many unaffected individuals, indicating that additional genetic and/or environmental factors are necessary for disease development. During the previous funding period we have made significant progress defining environmental exposures influencing XFS/XFG risk including time spent outdoors, residential latitude, UV light exposure, heavy coffee consumption and low folate intake. In collaboration with our international consortium, we have identified new genetic factors influencing risk including protective LOXL1 variants. We have also completed a metabolomics study using pre-diagnostic samples from the longitudinal Nurses’ Health Study (NHS) and Health Professionals Follow-up Study (HPFS) that identified 2 plasma metabolites classes (lysophosphatidylcholines and phosphatidylethanolamine plasmalogens), measured as much as a decade before disease onset, associated with increased XFS/XFG risk, and the individual metabolite cortisone and the metabolite classes of steroids and triglycerides inversely associated with risk. For the next funding period, we will build on these results using data from the NHS, NHS2 and HPFS, Mass Eye and Ear clinical case control set, and UK Biobank, to further define the complex set of risk factors contributing to this important blinding disease. We propose the following specific aims: 1) Investigate associations between steroids, lipid metabolites, environmental factors and XFS/XFG risk; 2) Investigate the contributions of rare/low frequency LOXL1 variants to XFS/XFG risk and 3) Evaluate integrated metabolomic and genomic effects on XFS/XFG risk. This unique study with comprehensive prospective environmental, genetic and metabolomic data and a multi-disciplinary team (expertise in genetics, metabolomics, epidemiology) will cost-efficiently address a significant cause of ocular morbidity. The findings will be directly relevant for clinical and public health practice.