Gene-Environment Interactions in Glaucoma

描述（由申请人提供）：我们建议在两个前瞻性随访的男性和女性队列中调查选定的基因-环境相互作用是否是原发性开角型青光眼（POAG）的危险因素。首先，我们将确定内皮型一氧化氮合酶基因（NOS3）的几种变异是否与POAG相关，采用从我们的研究人群中提取的巢式病例对照队列。然后，在单独的队列分析中，我们将在控制重要混杂因素后，使用分层和多变量技术研究激素替代疗法和饮酒与POAG的关系。最后，我们将回到我们的病例对照队列，以确定选定的NOS3多态性与我们的环境暴露之间的相互作用如何改变发生POAG的风险。护士健康研究（NHS）始于1976年，调查对象是121,700名年龄在30岁至55岁之间的妇女。1980年，大约89000名参与者完成了一份经过验证的半定量食物频率问卷（FFQ），此后每隔2-4年完成一次。卫生专业人员随访研究（HPFS）开始于1986年，在52,000名年龄在45-75岁之间的男性中，所有人在基线时完成FFQ，此后每4年完成一次。每两年向两组发送一份问卷，以更新暴露信息并报告包括POAG在内的主要疾病。关于绝经后激素使用、饮酒和其他相关协变量的信息已被反复收集。我们存储了来自NHS参与者的69,099个DNA样本和来自HPFS参与者的33,545个DNA样本。在拟议的研究中，我们将通过联系参与者的眼科保健提供者并从医疗记录中获取相关信息来确认POAG的报告。一个自我报告的POAG，将通过系统的记录回顾证实可重复的视野丧失与青光眼视神经病变一致。我们预计将发现1246例POAG病例，其中909例将有DNA样本可供分析。总的来说，前瞻性设计、大的队列规模、高随访率、反复评估已知会改变NOS3基因活性的暴露，以及仔细确认的POAG定义，为评估几个具有公共卫生重要性的假设提供了独特的机会。作为POAG决定因素的基因-环境相互作用的发现可能导致针对这种复杂疾病的基因型特异性一级预防策略。

DESCRIPTION (provided by applicant): We propose to investigate whether selected gene-environment interactions are risk factors for primary open angle glaucoma (POAG) in two prospectively followed cohorts of men and women. First, we will determine whether several variants of the endothelial nitric oxide synthase gene (NOS3) are associated with POAG using a nested case-control cohort drawn from our study population. Then, in separate cohort analyses we will study hormone replacement therapy and alcohol consumption in relation to POAG using stratified and multivariate techniques after controlling for important confounders. Finally, we will return to our case-control cohort to ascertain how the interaction between selected NOS3 polymorphisms and our environment exposure alters the risk of developing POAG. The Nurses' Health Study (NHS) began in 1976 among 121,700 women ranging in age from 30 to 55. Approximately 89,000 participants completed a validated semi quantitative food frequency questionnaire (FFQ) in 1980 and every 2-4 years since. The Health Professionals Follow-up Study (HPFS) began in 1986 among 52,000 men ranging in age from 45-75, all of whom completed a FFQ at baseline and every 4 years thereafter. Both groups have been sent a questionnaire biennially to update exposure information and report major illness including POAG. Information has been collected repeatedly on postmenopausal hormone use, alcohol consumption and other related covariates. We have 69,099 DNA samples from NHS participants and 33,545 DNA samples from HPFS participants in storage. In the proposed study we will confirm reports of POAG by contacting the participant's eye care provider, and obtaining pertinent information from the medical record. A self-report of POAG, will be confirmed by systematic record review documenting reproducible visual field loss consistent with glaucomatous optic neuropathy. We anticipate identifying 1246 POAG cases, 909 of which will have DNA samples available for analysis. Overall, the prospective design, large size of the cohorts, the high follow-up rates, repeated assessment of exposures known to alter NOS3 gene activity, and carefully confirmed POAG definition provide a unique opportunity to evaluate several hypotheses of public health importance. The discovery of gene-environment interactions that serve as determinants of POAG could lead to genotype-specific primary prevention strategies for this complex disease.