Genes and Environment Initiative in Glaucoma

描述（由申请人提供）：原发性开角型青光眼（POAG）是一种年龄相关的、眼内压（IOP）依赖性进行性视神经病变，最终导致失明。POAG的永久性视力丧失是一种具有公共卫生意义的疾病。目前的证据表明POAG是一种受环境影响而改变的多基因疾病。我们假设，通过全基因组关联研究（GWAS）识别和表征POAG易感基因将揭示影响疾病过程的重要环境决定因素，以及更好地了解基因-环境和基因-基因相互作用如何导致这种复杂的疾病。在本研究中，我们从三个队列中制定了病例对照研究人群：护士健康研究（NHS）;卫生专业人员随访研究（HPFS）;和马萨诸塞州眼耳医院（MEEI）。该队列包括1200例DMA病例和1200例对照。NHS和HPFS的成员也有16至24年期间的重复环境暴露数据。我们将进行单阶段GWAS并进行适当的统计分析，以找到与POAG相关性最强的遗传标记。我们确认顶级遗传标记的复制计划将涉及1400例病例和1400例对照的可比人群，其中一个重要的子集也将有重复的环境暴露数据。作为这项研究的一部分，我们将提交大量的环境暴露数据（来自NHS和HPFS的成员），这些数据可能会改变POAG的遗传易感性。这些结果将产生一个有价值的基因型，表型和环境暴露数据的集合，使科学家能够测试许多关于基因和环境如何与POAG事件相关的假设。这项研究也是更好地了解POAG潜在病理学的关键第一步，并将导致未来的建议，以检查在非裔美国人混合研究中高加索人群中发现的重要变异的相关性，进行精细绘图和重新测序高危人群中的候选基因，并研究POAG中的基因-基因相互作用。发现POAG中涉及的基因和环境相互作用的各种组合可能导致针对这种疾病的基因型特异性一级预防策略。

DESCRIPTION (provided by applicant): Primary open-angle glaucoma (POAG) is an age-related, intraocular pressure (lOP)-dependent progressive optic neuropathy that ultimately leads to blindness. Permanent vision loss from POAG is a condition of public health significance. Current evidence suggests that POAG is a polygenetic disease modified by environmental influences. We hypothesize that the identification and characterization of POAG susceptibility genes via a genome-wide association study (GWAS) will reveal significant environmental determinants that influence the disease process, as well as a better understanding of how gene-environment and gene-gene interactions contribute to this complex disease. For this study we have formulated a case-control study population from three cohorts: the Nurses Health Study (NHS); Health Professionals Follow-up Study (HPFS); and Massachusetts Eye and Ear Infirmary (MEEI). The cohort consists of 1200 cases and 1200 controls with DMA. Members of the NHS and HPFS also have repeated environmental exposure data over a 16 to 24 year period. We will perform a single-stage GWAS and carry out the appropriate statistical analyses to find genetic markers with the strongest association with POAG. Our replication plan to confirm the top genetic markers will involve a comparable population of 1400 cases and 1400 controls, a significant subset of which will also have repeated environmental exposure data. As part of this study, we will submit data on a myriad of environmental exposures (from members of NHS and HPFS) that could modify genetic predisposition for POAG to a central data repository. These results will generate a valuable collection of genotype, phenotype and environment exposure data, allowing scientists to test numerous hypotheses regarding how genes and environment relate to incident POAG. This study is also a crucial first step toward a better understanding of the underlying pathology responsible for POAG and will lead to future proposals to examine the relevance of the significant variants found in the Caucasian population in an African American admixture study, perform fine mapping and re-sequencing of candidate genes in at-risk populations, and investigate gene-gene interactions in POAG. Discovery of the various combinations of gene and environment interactions involved in POAG could lead to genotype-specific primary prevention strategies for this disease.