Genetic and Environmental Risk Factors for Exfoliation Syndrome and Glaucoma

描述（由申请人提供）：脱落综合征（ES）是一种常见的疾病，其特征是大分子的异质混合物沉积在整个眼睛前段。导致这种物质在ES中积累的因素尚不清楚。ES是一个公共卫生问题，因为它是高张力开角青光眼、早熟白内障形成和白内障手术并发症风险增加的危险因素。先前的研究表明，脱落综合征和相关的青光眼是遗传复杂的，其中一个基因LOXL1已被确定为主要的遗传危险因素。LOXL1基因变异在高达98%的患者中被发现；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，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。进一步的证据表明，LOXL1是必要的，但不是充分的，来自我们对LOXL1缺失小鼠的初步研究，确定了一些，但不是所有的表型特征。为了确定导致脱落综合征和脱落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，对2300例脱落病例和2300例对照组进行了研究。650例病例和2250例对照已完成全基因组基因分型，1000多例病例有详细的环境暴露。我们将进行单阶段GWAS，以确定与脱落综合征相关的其他遗传标记，并将调查ES与环境暴露之间的关系，包括居住在北纬地区影响同型半胱氨酸水平的因素。新发现的遗传和环境危险因素将分析基因-环境和基因-基因相互作用。

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.