Gene-Environment Interactions in Glaucoma

描述（由申请人提供）：原发性开角型青光眼（POAG）是一种眼压（IOP）依赖的缓慢进展的视神经病变，最终导致失明。基于人群的调查数据表明，通过眼血流动力学测试、眼灌注压测量和血管内皮功能障碍标志物评估的血管功能障碍在青光眼中很重要。此外，通过绝经年龄和绝经后激素使用来评估的女性生殖特性也可能在POAG中发挥作用。在这篇论文中，我们建议通过研究血管功能障碍和雌激素水平与POAG相关的关键基因环境相互作用，进一步探索先前资助工作的重要发现。为了研究血管功能障碍，我们打算使用来自5项研究（护士健康研究[NHS]、卫生专业人员随访研究[HPFS]、Mass Eye and Ear Infirmary、妇女健康研究[WHS]和NEIGHBOR联盟）的高密度全基因组基因分型数据，选择一组专门参与介导血管紧张的基因标记，并确定与POAG相关的最高单核苷酸多态性（snp）。其次，我们将延长NHS和HPFS参与者的随访至2014年，并使用嵌套病例对照组研究内皮功能障碍生物标志物（ICAM-1、e -选择素和TNF α）与POAG事件之间的关系。最后，我们将使用来自NHS和HPFS的病例对照组，评估介导血管张力的顶级snp是否与POAG中内皮功能障碍的生物标志物相互作用。由于雌激素影响血管张力，我们还将在NHS和WHS的女性中评估介导血管张力的顶级snp与女性生殖属性之间的相互作用（见下文）。为了进一步探索性别生物学，我们提出了一项前瞻性队列研究，以评估女性生殖特征（初潮年龄、胎次和口服避孕药使用）与NHS参与者POAG风险之间的关系。然后，我们将利用这5项研究中已有的高密度全基因组基因分型数据，评估基因在雌激素代谢途径中的作用。最后，由于影响雌激素水平的基因-环境相互作用可能参与了POAG，我们计划确定在NHS和WHS中，雌激素代谢最高的snp是否与女性生殖健康的各种属性相互作用。基因和环境因素的结合将性别生物学和血管功能障碍与POAG联系起来，这一发现可能会为该疾病带来更合理的治疗方法。此外，这项研究可能导致基因型特异性生活方式改变策略来预防POAG。

DESCRIPTION (provided by applicant): Primary open-angle glaucoma (POAG) is an intraocular pressure (IOP)-dependent, slowly progressive optic neuropathy that ultimately leads to blindness. Data from population-based surveys demonstrate that vascular dysfunction, as assessed with ocular hemodynamic testing, measurements of ocular perfusion pressure and markers of vascular endothelial dysfunction, is important in glaucoma. Furthermore, female reproductive attributes, as assessed by age at menopause and postmenopausal hormone use, may also play a role in POAG. In this Resubmission:, we propose to further explore important findings from the previously funded work, by examining key gene environment interactions of vascular dysfunction and estrogen levels in relation to POAG. For the study of vascular dysfunction, we intend to use pre-existing high density whole genome-wide genotyping data from 5 studies (Nurses Health Study [NHS], Health Professionals Follow-up Study [HPFS], Mass Eye and Ear Infirmary, Women's Health Study [WHS] and the NEIGHBOR consortium) to select a panel of markers in genes specifially involved in mediating vascular tone, and identify the top single nucleotide polymorphisms (SNPs) associated with POAG. Second, we will extend the follow-up of NHS and HPFS participants to 2014, and study the relation between biomarkers of endothelial dysfunction (ICAM-1, E-selectin and TNF alpha) and incident POAG, using a nested case control group. Finally, we will assess whether the top SNPs mediating vascular tone interact with biomarkers of endothelial dysfunction in POAG using a case control group from NHS and HPFS. Since estrogen influences vascular tone, we will also assess interactions between the top SNPs mediating vasuclar tone and attributes of female reproduction (see below), among women in the NHS and WHS. To further explore gender biology we propose a prospective cohort study to assess the relationship between female reproductive attributes (age at menarche, parity and oral contraceptive use) and POAG risk among NHS participants. Then, we will evaluate the role of genes in the estrogen- metabolizing pathway, by using the pre-existing high density whole genome-wide genotyping data from the 5 studies. Finally, as gene-environment interactions that influence estrogen levels may be involved in POAG, we plan to ascertain whether the top estrogen metabolizing SNPs interact with various attributes of female reproductive health among women in the NHS and WHS. The discovery of the combination of genetic and environment factors that serve to link gender biology and vascular dysfunction to POAG could lead to more rationale treatments for the disease. Furthermore, this research could lead to genotype-specific lifestyle modification strategies to prevent POAG. PUBLIC HEALTH RELEVANCE: The overall goal of this research is to assess the relation between vascular dysfunction, gender biology and primary open angle glaucoma (POAG), the most common form of glaucoma in the Western world and a leading cause of blindness. We will use 5 datasets with detailed genotype and phenotype information to accelerate the discovery of gene- environment interactions in POAG that are related to vascular tone and estrogen metabolism. The discovery of the combination of genetic and environment factors that link vascular dysfunction, gender biology and POAG could lead to more effective treatments for this potentially blinding condition.