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，其特征在于 异常纤维蛋白聚集体，与青光眼（XFG）、早熟白内障 形成和白内障手术期间的并发症以及几种全身性疾病。我们的目标是 阐明剥脱综合征（XFS）和相关青光眼（XFG）的发病机制， 促进有效的筛查和预防策略以及新疗法的开发。聚合 L0 XL 1是致病性纤维聚集体的一种组分，并且L0 XL 1是致病性纤维聚集体的主要遗传风险因子。 XFS/XFG，其中LOXL 1风险变体发生在高达98%的患者中。然而，XFS/XFG在基因上 复杂，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，表明 另外的遗传和/或环境因素是疾病发展所必需的。前一 我们在界定影响XFS/XFG风险的环境风险方面取得了重大进展 包括户外活动时间、居住纬度、紫外线照射、大量饮用咖啡和低叶酸 摄入通过与我们的国际联盟合作，我们已经确定了影响风险的新遗传因素。 包括保护性LOXL 1变体。我们还完成了一项代谢组学研究， 样本来自护士健康纵向研究（NHS）和卫生专业人员随访研究（HPFS） 鉴定了2种血浆代谢物类别（溶血磷脂酰胆碱和磷脂酰乙醇胺 在发病前十年测量，与XFS/XFG增加相关 风险，和个别代谢物可的松和代谢物类别的类固醇和甘油三酯成反比 与风险相关。在下一个资助期，我们将利用NHS的数据， 和HPFS、Mass Eye and Ear临床病例对照集和UK Biobank，以进一步定义 导致这种重要致盲疾病的危险因素。我们提出以下具体目标：1） 研究类固醇、脂质代谢物、环境因素与XFS/XFG风险之间的关系; 2） 研究罕见/低频率LOXL 1变异体对XFS/XFG风险的贡献，3）评估综合 代谢组学和基因组对XFS/XFG风险的影响。这项独特的研究具有全面的前瞻性 环境，遗传和代谢组学数据和多学科团队（遗传学专业知识， 代谢组学、流行病学）将成本有效地解决眼部发病的重要原因。这些发现 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.