Genetic and Environmental Risk Factors for Exfoliation Syndrome and Glaucoma

剥脱综合征（XFS）是导致高眼压性开角型青光眼（XFG）的常见病症， 成熟白内障形成和白内障手术期间的并发症。有证据表明，XFS/XFG是 基因复杂LOXL 1是XFS/XFG的主要遗传风险因素，LOXL 1变异体发生在高达 98%的患者。然而，这些相同的变异也存在于高达80%的未受影响的个体中， 表明额外的遗传和/或环境因素对于疾病发展是必要的。我们 目标是全面定义XFS/XFG的风险因素（遗传和环境）， 促进有效的筛查和预防策略以及新疗法的开发。上一 资助期间，使用来自护士健康研究（NHS）和健康 专业人士跟踪研究（HPFS），我们已经确定了主要的环境暴露显着 影响XFS/XFG的风险，包括户外活动时间，大量咖啡消费和低饮食 叶酸摄入量（与同型半胱氨酸升高有关）。使用来自Mass Eye and Ear的病例对照样本， 我已经评估了CLU变体对XFS/XFG的贡献，并为一项国际研究做出了贡献 CACNA 1A是一种新的遗传风险因子。我们从美国7个不同的地点收集了DNA样本 对1241例XFS/XFG病例进行了基因分型，并对常见和罕见SNP进行了全基因组基因分型 在CIDR。在NHS和HPFS中，我们预计在10万多名参与者中发生600例XFS/XFG病例 前瞻性随访了30多年。在下一个资助期内，我们建议的具体目标如下： 完成遗传分析，以确定XFS/XFG的新遗传风险因素，包括罕见的 变异和探索复杂的遗传相互作用; 2）调查环境暴露的作用， 同型半胱氨酸（DASH饮食模式）和紫外线暴露，并探索与LOXL的相互作用1，和3） 完成XFS/XFG的首次诊断前代谢组学分析，重点关注与以下相关的代谢物： 高半胱氨酸和叶酸以及单个代谢物与LOXL 1的相互作用。这项拟议的研究是 重要的是，它有望推进和扩大我们对遗传病因学的理解。 XFS/XFG，因为它将利用来自大型病例/对照研究的数据进行遗传分析，并且将是第一项研究 拷贝数变异和罕见变异的基因该项目具有创新性和应用前景 收集环境暴露数据和用于NHS/HPFS代谢组学研究的预诊断血清， 调查疾病发展前病例中存在的因素。总的来说，这些研究将推动我们的 了解可能成为治疗靶点和疾病风险生物标志物的易感事件。

Exfoliation syndrome (XFS) is a common condition that causes high-tension open-angle glaucoma (XFG), pre- mature cataract formation, and complications during cataract surgery. Evidence suggests that XFS/XFG is genetically complex. LOXL1 is a major genetic risk factor for XFS/XFG, with LOXL1 variants occurring in up to 98% of patients. However, these same variants are also present in up to 80% of unaffected individuals, indicating that additional genetic and/or environmental factors are necessary for disease development. Our goal is to comprehensively define risk factors (both genetic and environmental) for XFS/XFG, which will facilitate effective screening and prevention strategies and the development of novel therapies. In the previous funding period, using data from large ongoing prospective cohorts of Nurses' Health Study (NHS) and Health Professionals Follow-up Study (HPFS), we have identified major environmental exposures significantly influencing the risk of XFS/XFG including time spent outdoors, heavy coffee consumption and low dietary folate intake (related to elevated homocysteine). Using a case control sample from Mass Eye and Ear, we have assessed the contributions of CLU variants to XFS/XFG and have contributed to an international study identifying CACNA1A as a novel genetic risk factor. From 7 different US sites, we have collected DNA samples for 1241 XFS/XFG cases and genome-wide genotyping for both common and rare SNPs has been completed at CIDR. In NHS and HPFS, we project to have incident 600 cases of XFS/XFG among 100,000+ participants followed prospectively for 30+ years. For the next funding period, we propose the following specific aims: 1) complete genetic analyses to identify new genetic risk factors for XFS/XFG, including contributions of rare variants and explore complex genetic interactions; 2) investigate the role of environmental exposures related to homocysteine (DASH dietary pattern) and UV light exposure and explore interactions with LOXL1, and 3) complete the first pre-diagnostic metabolomic analysis for XFS/XFG focusing on metabolites related to homocysteine and folate and interactions for individual metabolites with LOXL1. This proposed research is significant because it is expected to advance and expand our understanding of the genetic etiology of XFS/XFG as it will leverage data from a large case/control study for genetic analyses and will be the first study of copy number variants and rare variants for this condition. The project is innovative in using prospectively collected environmental exposure data and pre-diagnostic serum for metabolomic studies in NHS/HPFS, to investigate factors present in cases prior to disease development. Overall these studies will advance our understanding of the predispoing events that could be therapeutic targets and biomarkers of disease risk.