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。我们以前的工作表明，一氧化氮(NO)信号的受损，加上雌激素水平的下降，加剧了POAG患者内皮细胞-平滑肌通讯功能的障碍。在这项提案中，利用护士健康研究(NHS)的资源，我们将比较患有和不患有POAG的绝经后妇女的循环雌激素水平。绝经年龄有遗传基础，年龄越大，患POAG的风险越低。使用国家眼科研究所青光眼人类遗传学合作遗传总体操作数据库(Neighbor)的数据，我们将评估与绝经年龄相关的遗传易感性评分是否与POAG有关。最后，我们还将评估雌激素代谢途径中的特定基因类型是否与POAG患者的血清雌激素水平相互作用。我们的数据表明，CAV1/CAV2的基因组变异与POAG有关。CAV1/CAV2编码内皮细胞膜上并列的小窝蛋白和一氧化氮合酶3(NOS3)。他汀类药物的使用可能会调节内皮细胞中小窝蛋白和NO信号之间的功能相互作用，从而有利于改变青光眼的风险。我们将在NHS、NHS2和卫生专业人员随访研究(HPFS)中对目前他汀类药物的使用与POAG之间的关系进行前瞻性队列分析。我们还将评估他汀类药物的使用是否与POAG中CAV1/CAV2和NOS3的常见变体相互作用。我们将把我们对与内皮细胞功能相关的环境因素的分析扩展到饮食中的生物黄酮类化合物，它们是已知的改变内皮细胞功能的物质。有证据表明，POAG患者的初始中心旁视野丧失存在内皮细胞功能障碍，但对POAG患者中心旁视野丧失的环境决定因素知之甚少。我们在伴有中心旁视野丧失的POAG患者中发现了两个内皮细胞功能障碍的遗传生物标志物：CAV1/CAV2，GUCY1A3/GUCY1B3。我们将评估改变内皮细胞功能的因素，如高血压和绝经后激素使用，是否与这种青光眼内表型有关。开角型青光眼是一种有着复杂病理网络的疾病。这项建议利用与NHS、NHSII、HPFS和邻近地区的内皮细胞功能障碍和雌激素代谢相关的丰富生物标记物来解开这张网。该提案旨在确定和制定更合理的POAG预防战略和干预措施。

DESCRIPTION (provided by applicant): Primary open-angle glaucoma (POAG) is an intraocular pressure (IOP) - dependent, slowly progressive optic neuropathy that ultimately leads to blindness. Our prior work suggests that impaired nitric oxide (NO) signaling, exacerbated by declining estrogen levels contributes to dysfunctional endothelial cell - smooth muscle communication in POAG. In this proposal, using resources from the Nurses Health Study (NHS), we will compare circulating estrogen levels in postmenopausal women with and without POAG. Age at menopause has a genetic basis, and later age has been associated with reduced risk of POAG. Using data from the National Eye Institute Glaucoma Human Genetics Collaboration Heritable Overall Operational Database (NEIGHBORHOOD), we will evaluate whether a genetic predisposition score related to age at menopause is associated with POAG. Finally, we will also assess whether specific genotypes in the estrogen metabolic pathway interact with serum estrogen levels in POAG. Our data indicate that genomic variants in CAV1/CAV2, which codes for caveolins juxtaposed to NO synthase 3 (NOS3) in endothelial cell membranes, are related to POAG. Statin use may modulate the functional interaction between caveolin and NO signaling in endothelial cells to favorably alter glaucoma risk. We will perform a prospective cohort analysis of the relation between current statin use and POAG in NHS, NHS2 and the Health Professionals Follow-up Study (HPFS). We will also evaluate whether statin use interacts with common variants of CAV1/CAV2 and NOS3 in POAG. We will extend our analysis of environmental factors related to endothelial cell function to dietary bioflavonoids, which are known to alter endothelial cell function. There is evidence that POAG patients with initial paracentral visual field loss have endothelial cell dysfunction, yet little is known regarding environmental determinants of paracentral visual field loss in POAG. We have discovered two genetic biomarkers of endothelial cell dysfunction in POAG patients with paracentral visual field loss: CAV1/CAV2, GUCY1A3 / GUCY1B3. We will assess if factors that alter endothelial cell function, such as hypertension and postmenopausal hormone use, are associated with this glaucoma endophenotype. POAG is disease with a complex web of pathology. This proposal draws on the wealth of biomarkers related to endothelial cell dysfunction and estrogen metabolism in NHS, NHSII, HPFS and the NEIGHBORHOOD to dis- entangle that web. The proposal aims to identify and develop more rational preventive strategies and interventions for POAG.