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: 8185917
• 负责人: Janey L Wiggs
• 金额: $ 78.04万
• 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 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8185917
• 关键词: Affect; Alleles; Anterior eyeball segment structure; Aqueous Humor; Caffeine; Case-Control Studies; Cataract; Cataract Extraction; Climate; Clinic; Complex; Consumption; Data; Deposition; Development; Dietary Factors; Disease; Ear; Environment; Environmental Exposure; Environmental Risk Factor; Evaluation; Exfoliation Syndrome; Eye; Folate; Frequencies; Genes; Genetic; Genetic Markers; Genetic Risk; Genetic Variation; Genome; Genomics; Genotype; German population; Glaucoma; Goals; Health; Health Professional; Homocysteine; Homocystine; Individual; Intake; Knockout Mice; Life; Massachusetts; Meta-Analysis; Morbidity - disease rate; Nurses' Health Study; Open-Angle Glaucoma; Pathogenesis; Patients; Physicians; Plasma; Population Study; Prevention strategy; Public Health; Recording of previous events; Regulation; Relative Risks; Research; Resources; Risk; Risk Factors; Sampling; Screening procedure; Single Nucleotide Polymorphism; Smoking; Staging; Testing; Translating; United States; Universities; Variant; Vitamin B 12; Vitamin B6; Woman; base; case control; disorder risk; follow-up; gene environment interaction; gene interaction; genetic epidemiology; genetic risk factor; genetic variant; genome wide association study; genome-wide; hazard; macromolecule; novel; novel strategies; population based; residence

DESCRIPTION (provided by applicant): Exfoliation syndrome (ES) is a common condition characterized by deposition of a heterogeneous mix of macromolecules throughout the anterior segment of the eye. The factors that cause this material to accumulate in ES remain unknown. ES is a public health problem, because it is a risk factor for high-tension open-angle glaucoma, pre-mature cataract formation, and increased risk of complications during cataract surgery. Previous studies suggest that exfoliation syndrome and the related glaucoma are genetically complex, and one gene, LOXL1, has been identified as a major genetic risk factor. LOXL1 gene variants are found in up to 98% of affected 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. Further evidence that LOXL1 is necessary but not sufficient for the disease comes from our preliminary studies of the LOXL1 null mouse that identified some, but not all the phenotypic features of the condition. To identify additional genetic and environmental factors contributing to exfoliation syndrome and exfoliation glaucoma, we have formed a collaborative consortium contributing over 2300 exfoliation cases and 2300 controls. Whole genome genotyping has already been completed in 650 cases and 2250 controls, and over 1000 cases have detailed environmental exposures. We will perform a single stage GWAS to identify additional genetic markers associated with exfoliation syndrome, and will also investigate associations between ES and environmental exposures including factors that influence homocysteine levels the effect of residence in northern latitude. Newly discovered genetic and environmental risk factors will be analyzed for gene- environment and gene-gene interactions. PUBLIC HEALTH RELEVANCE: Exfoliation syndrome is a common condition that causes significant ocular morbidity, and in particular is associated with a severe form of glaucoma. One gene, LOXL1 is known to contribute to this condition, but the high frequency of the LOXL1 risk genotype in normal individuals indicates that other factors are required for disease development. The overall goal of this project is to identify additional factors that contribute to exfoliation, which may be genetic and/or environmental, and may be additive or protective. The identification of new factors can translate into screening tests, and novel strategies for treatment.

描述（由申请人提供）：剥脱综合症（ES）是一种常见病症，其特征是整个眼前节中大分子的异质混合物沉积。导致这种物质在 ES 中积累的因素仍然未知。 ES是一个公共健康问题，因为它是高眼压开角型青光眼、过早白内障形成以及白内障手术期间并发症风险增加的危险因素。先前的研究表明，剥脱性综合征和相关的青光眼在遗传上很复杂，其中一个基因 LOXL1 已被确定为主要的遗传危险因素。 LOXL1 基因变异存在于高达 98% 的受影响患者中；然而，这些相同的变异也存在于高达 80% 的未受影响个体中，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。 LOXL1对于该疾病是必要的但还不够的进一步证据来自我们对LOXL1缺失小鼠的初步研究，该研究鉴定了该疾病的一些但不是全部表型特征。为了确定导致剥脱性综合征和剥脱性青光眼的其他遗传和环境因素，我们成立了一个合作联盟，提供了 2300 多个剥脱性病例和 2300 多个对照。已完成 650 例病例和 2250 例对照的全基因组基因分型，超过 1000 例病例有详细的环境暴露情况。我们将进行单阶段 GWAS 来识别与剥脱综合征相关的其他遗传标记，还将研究 ES 与环境暴露之间的关联，包括影响同型半胱氨酸水平的因素以及居住在北纬地区的影响。将分析新发现的遗传和环境风险因素的基因-环境和基因-基因相互作用。 公众健康相关性：剥脱综合征是一种常见病症，会导致严重的眼部发病，尤其与严重的青光眼有关。已知一个基因 LOXL1 会导致这种情况，但正常个体中 LOXL1 风险基因型的高频率表明疾病的发展需要其他因素。该项目的总体目标是确定导致剥落的其他因素，这些因素可能是遗传和/或环境的，也可能是添加剂或保护性的。新因素的识别可以转化为筛查测试和新的治疗策略。