Genetic and Environmental Risk Factors for Exfoliation Syndrome and Glaucoma

剥脱性综合征和青光眼的遗传和环境风险因素

• 批准号: 10013224
• 负责人: Janey L Wiggs
• 金额: $ 39.85万
• 依托单位: MASSACHUSETTS EYE AND EAR INFIRMARY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10013224
• 关键词: Address; Adherence; Age; Blindness; Caffeine; Case-Control Studies; Cataract; Cataract Extraction; Climate; Coffee; Complex; Consumption; Copy Number Polymorphism; DASH diet; DNA; Data; Data Analyses; Data Set; Development; Diagnostic; Diet; Dietary Practices; Disease; Ear; Environmental Exposure; Environmental Risk Factor; Etiology; Event; Exfoliation Syndrome; Exposure to; Eye; Family; Folic Acid; Follow-Up Studies; Functional disorder; Funding; Future; Gene Frequency; Genes; Genetic; Genetic Predisposition to Disease; Genetic Risk; Genomic Segment; Genotype; Glaucoma; Goals; Haplotypes; Health Professional; Homocysteine; Individual; Intake; International; Measures; Mediating; Metabolism; Minor; Molecular; Nurses' Health Study; Onset of illness; Open-Angle Glaucoma; Other Genetics; Participant; Pathogenesis; Pathway Analysis; Pathway interactions; Patients; Plasma; Prevention strategy; Prevention therapy; Primary Prevention; Prospective cohort; Public Health; Recording of previous events; Research; Resolution; Risk; Risk Factors; Role; Sampling; Serum; Site; Skin Carcinoma; Systemic disease; Time; UV Radiation Exposure; Ultraviolet Rays; Variant; age related; case control; curative treatments; disease phenotype; disorder risk; genetic analysis; genetic risk factor; genetic testing; genome wide association study; genome-wide; innovation; insight; member; metabolomics; new therapeutic target; novel; novel therapeutics; premature; prospective; protein aggregation; rare variant; screening; targeted biomarker; therapeutic target

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.

剥脱性综合征 (XFS) 是导致高眼压开角型青光眼 (XFG) 的常见病症， 成熟的白内障形成以及白内障手术期间的并发症。有证据表明 XFS/XFG 是 基因复杂。 LOXL1 是 XFS/XFG 的主要遗传风险因素，LOXL1 变异发生在多达 98%的患者。然而，这些相同的变异也存在于高达 80% 的未受影响个体中， 表明额外的遗传和/或环境因素对于疾病的发展是必要的。我们的 目标是全面定义 XFS/XFG 的风险因素（遗传和环境），这将 促进有效的筛查和预防策略以及新疗法的开发。在之前的 资助期，使用来自护士健康研究 (NHS) 和健康的大型持续前瞻性队列的数据 专业人士跟踪研究（HPFS），我们显着识别了主要环境暴露 影响 XFS/XFG 风险的因素包括户外时间、大量咖啡摄入和低饮食 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，我们 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 将 CACNA1A 确定为一种新的遗传风险因素。我们从美国 7 个不同地点收集了 DNA 样本 已完成 1241 个 XFS/XFG 病例的常见和罕见 SNP 的全基因组基因分型 在CIDR。在 NHS 和 HPFS 中，我们预计 100,000 多名参与者中将发生 600 例 XFS/XFG 病例 前瞻性地跟踪了 30 多年。对于下一个资助期，我们提出以下具体目标：1) 完整的遗传分析，以确定 XFS/XFG 的新遗传风险因素，包括罕见的贡献 变异并探索复杂的遗传相互作用； 2) 调查相关环境暴露的作用 同型半胱氨酸（DASH 饮食模式）和紫外线照射，并探索与 LOXL1 和 3) 的相互作用 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 同型半胱氨酸和叶酸以及单个代谢物与 LOXL1 的相互作用。这项拟议的研究是 意义重大，因为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 这种情况的拷贝数变异和罕见变异。该项目的创新之处在于前瞻性地利用 收集环境暴露数据和诊断前血清用于 NHS/HPFS 的代谢组学研究， 研究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 了解可能成为治疗目标和疾病风险生物标志物的诱发事件。