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）依赖性、缓慢进行性视神经病变，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评估的女性生殖属性也可能在 POAG 中发挥作用。在本次重新提交中，我们建议通过检查与 POAG 相关的血管功能障碍和雌激素水平的关键基因环境相互作用，进一步探索先前资助的工作的重要发现。对于血管功能障碍的研究，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]、大众眼耳医院、妇女健康研究 [WHS] 和 NEIGHBOR 联盟）的现有高密度全基因组基因分型数据来选择专门参与介导血管张力的基因中的一组标记，并确定最重要的单核苷酸多态性(SNP) 与 POAG 相关。其次，我们将 NHS 和 HPFS 参与者的随访时间延长至 2014 年，并使用巢式病例对照组研究内皮功能障碍的生物标志物（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 的病例对照组来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，我们还将评估 NHS 和 WHS 女性中调节血管张力的主要 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（初潮年龄、产次和口服避孕药的使用）与 POAG 风险之间的关系。然后，我们将利用来自 5 项研究的现有高密度全基因组基因分型数据来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 相关，我们计划确定雌激素代谢最高的 SNP 是否与 NHS 和 WHS 女性生殖健康的各种属性相互作用。将性别生物学和血管功能障碍与 POAG 联系起来的遗传和环境因素的结合的发现可能会导致对该疾病的更合理的治疗。此外，这项研究可能会导致针对基因型的生活方式改变策略来预防 POAG。 公共健康相关性：本研究的总体目标是评估血管功能障碍、性别生物学和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 个包含详细基因型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-环境相互作用。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结合的发现可能会为这种潜在致盲疾病提供更有效的治疗方法。

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.