Gene-Environment Interactions in Glaucoma

摘要原发性开角型青光眼(POAG)是一种依赖眼压(IOP)、进展缓慢的视神经疾病。 最终导致失明的神经病。基于人群的调查数据表明，血管 通过眼血流动力学测试、眼血流灌注压和眼压的测量来评估功能障碍 血管内皮细胞功能障碍的标志物，在青光眼中很重要。此外，女性生殖能力 根据绝经年龄和绝经后激素使用情况评估的属性也可能在 普阿格。在这次重新提交中，我们建议进一步探索以前资助的工作的重要发现， 通过检查与血管功能障碍和雌激素水平相关的关键基因环境的交互作用 普阿格。对于血管功能障碍的研究，我们打算使用预先存在的高密度全基因组 5项研究的基因分型数据(护士健康研究[NHS]，卫生专业人员随访研究[HPFS]， MASS眼耳医院、妇女健康研究[WHS]和邻居联盟)来选择小组 在特定参与调节血管张力的基因中的标记，并识别最上面的单核苷酸 与开角型青光眼相关的多态(SNP)。第二，我们将延长NHS和HPFS的后续行动 2014年，研究内皮功能障碍的生物标志物(ICAM-1、E-选择素)之间的关系 和肿瘤坏死因子α)和事件POAG，采用嵌套病例对照组。最后，我们将评估是否 介导血管张力的TOP SNP与POAG患者内皮功能障碍的生物标志物相互作用 对照组来自NHS和HPFS。由于雌激素影响血管张力，我们也将评估相互作用。 在调节血管张力和女性生殖属性的顶端SNPs之间(见下文)， NHS和WHS中的女性。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 评估女性生殖属性(初潮年龄、产次和口服避孕药)之间的关系 使用)和英国国民健康保险制度参与者的POAG风险。然后，我们将评估基因在雌激素中的作用- 代谢途径，通过使用来自5个国家的先前存在的高密度全基因组基因数据 学习。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 计划确定顶层雌激素代谢的SNPs是否与女性的各种属性相互作用 NHS和WHS中妇女的生殖健康。基因和基因结合的发现 将性别生物学和血管功能障碍与POAG联系起来的环境因素可能会导致更多 治疗这种疾病的基本原理。此外，这项研究可能会导致特定于基因型的生活方式 预防POAG的修改策略。

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.