Gene-Environment Interactions in Glaucoma

描述（由申请人提供）：原发性开角型青光眼（POAG）是一种眼内压（IOP）依赖性、缓慢进展的视神经病变，最终导致失明。我们之前的研究表明，一氧化氮（NO）信号受损，雌激素水平下降加剧了POAG中内皮细胞-平滑肌通信功能障碍。在这项建议中，我们将利用护士健康研究（NHS）的资源，比较绝经后妇女有和没有POAG的循环雌激素水平。绝经年龄有遗传基础，年龄越晚患POAG的风险越低。使用来自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（NEIGHBORHOOD）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相关。最后，我们还将评估雌激素代谢途径中的特定基因型是否与POAG的血清雌激素水平相互作用。我们的数据表明，内皮细胞膜中与NO合成酶3 （NOS3）并列的CAV1/CAV2编码的基因组变异与POAG有关。他汀类药物的使用可能调节内皮细胞中小窝蛋白和NO信号之间的功能相互作用，从而有利地改变青光眼的风险。我们将在NHS、NHS2和卫生专业人员随访研究（HPFS）中对当前他汀类药物使用与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是否与POAG中常见的CAV1/CAV2和NOS3变体相互作用。我们将把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类黄酮，它已知会改变内皮细胞的功能。有证据表明，POAG患者初始中央旁视野丧失有内皮细胞功能障碍，但对于POAG患者中央旁视野丧失的环境决定因素知之甚少。我们发现了POAG合并中央旁视野丧失患者内皮细胞功能障碍的两个遗传生物标志物：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的使用，是否与这种青光眼内表型有关。POAG是一种具有复杂病理网络的疾病。该建议利用NHS、NHSII、HPFS和NEIGHBORHOOD中与内皮细胞功能障碍和雌激素代谢相关的大量生物标志物来解开这一网络。该建议旨在为POAG确定和制定更合理的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.