Gene-Environment Interactions in Glaucoma

描述(申请人提供)：原发性开角型青光眼(POAG)是一种依赖眼压(IOP)的缓慢进展的视神经病变，最终导致失明。来自人群调查的数据表明，通过眼血流动力学测试、眼血流灌注压测量和血管内皮功能障碍标志物来评估血管功能障碍对青光眼很重要。此外，根据绝经年龄和绝经后激素使用评估的女性生殖属性也可能在POAG中发挥作用。在这次重新提交中，我们建议通过检查血管功能障碍和雌激素水平与POAG相关的关键基因环境的交互作用，进一步探索来自先前资助工作的重要发现。对于血管功能障碍的研究，我们打算使用现有的5项研究(护士健康研究[NHS]、卫生专业人员跟踪研究[HPFS]、大众眼耳医院、妇女健康研究[WHS]和邻近联盟)的高密度全基因组基因分型数据来选择一组特定参与调节血管张力的基因的标记，并确定与POAG相关的顶级单核苷酸多态(SNPs)。其次，我们将NHS和HPFS参与者的随访延长到2014年，并使用嵌套病例对照组研究内皮功能障碍的生物标记物(ICAM-1、E-选择素和肿瘤坏死因子α)与POAG事件的关系。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SNPs是否与POAG患者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，我们还将评估NHS和WHS中调节血管张力的顶级SNP与女性生殖属性(见下文)之间的相互作用。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NHS参与者中女性生殖属性(月经初潮年龄、产次和口服避孕药使用)与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-环境相互作用可能与POAG有关，我们计划确定在NHS和WHS中，顶端雌激素代谢的SNPs是否与女性生殖健康的各种属性相互作用。遗传和环境因素的组合有助于将性别生物学和血管功能障碍与POAG联系起来，这一发现可能会导致对这种疾病进行更合理的治疗。此外，这项研究可能导致针对基因型的生活方式改变策略来预防POAG。 公共卫生相关性：这项研究的总体目标是评估血管功能障碍、性别生物学与原发性开角型青光眼(POAG)之间的关系。POAG是西方世界最常见的青光眼形式，也是导致失明的主要原因。我们将使用5个包含详细的基因和表型信息的数据集来加速发现POAG中与血管张力和雌激素代谢相关的基因-环境交互作用。发现将血管功能障碍、性别生物学和POAG联系起来的遗传和环境因素的组合，可能会为这种潜在的致盲疾病带来更有效的治疗方法。

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.