Understanding the clinical impact of cumulative genetic risk to glaucoma

了解累积遗传风险对青光眼的临床影响

• 批准号: 10183669
• 负责人: Louis Robert Pasquale
• 金额: $ 73.21万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10183669
• 关键词: Affect; Age; Aging; Area; Attention; Blindness; Candidate Disease Gene; Cardiovascular Diseases; Case-Control Studies; Characteristics; Chronic; Clinical; Collaborations; Complex; Consensus; Consent; Data; Databases; Derivation procedure; Detection; Diabetes Mellitus; Diagnosis; Diagnostic tests; Discipline; Disease; Disease Outcome; Disease Progression; Early Diagnosis; Electronic Health Record; Environmental Exposure; Environmental Risk Factor; Estrogens; Ethnic Origin; Evaluation; Follow-Up Studies; Frequencies; Fundus photography; Genetic; Genetic Risk; Genotype; Glaucoma; Goals; Health Professional; Health Status; Healthcare; Heritability; Hospitals; Human Genetics; Individual; Intake; International; Knowledge; Linkage Disequilibrium; Longitudinal Studies; Measures; Medical; National Eye Institute; Nerve Fibers; Nurses' Health Study; Oral health; Patient-Focused Outcomes; Patients; Pattern; Persons; Phenotype; Physiologic Intraocular Pressure; Population; Prevalence; Prevention; Prevention strategy; Primary Open Angle Glaucoma; Progressive Disease; Receiver Operating Characteristics; Recording of previous events; Research; Risk; Role; Sample Size; Sampling; Screening procedure; Site; Source; Sum; Testing; Time; Translating; United States National Institutes of Health; Variant; Vegetables; Visual Fields; Weight; Women' s Health; Work; aged; base; biobank; clinical phenotype; clinically relevant; dietary nitrate; disorder prevention; disorder risk; endophenotype; ethnic diversity; field study; gene discovery; genetic information; genetic variant; genome wide association study; genomic locus; improved; insight; medical schools; multi-ethnic; novel; optic nerve disorder; personalized approach; polygenic risk score; population based; precision medicine; prevent; programs; research clinical testing; risk variant; screening; sex; study population; tomography; tool

Primary open-angle glaucoma (POAG), the most common glaucoma subtype, is a prototypical common complex disease with a strong polygenetic component. This proposal is aligned with the NIH roadmap, leveraging the decade-long effort of gene discovery for POAG into precision medicine approaches that facilitate an early glaucoma diagnosis while outlining strategies to prevent glaucoma-related blindness. In this study, we propose 3 specific aims. 1) We will assemble all of the common gene variants discovered for POAG over the past decade into a multi-ancestry panel to test whether they predict glaucoma in 4 independent study populations (the UK Biobank, a health professional case-control study embedded in a population based sample, and patients from 2 hospital-based biobanks (total sample size: over 12,000 POAG cases in ~600,286 subjects). 2) Hospital-based biobanks offer an opportunity to contributed precision based medical knowledge about glaucoma. We will invite 800 patients from two hospital-based biobanks with low and high glaucoma polygenetic risk score (PRS) for systematic clinical evaluation. This detailed phenotype-genotype correlation will provide unique insights into glaucoma and will demonstrate the utility of such biobanks to identify previously undiagnosed disease, an unmet need in the field of glaucoma. 3) While a glaucoma PRS is probably the strongest predictor of glaucoma, we anticipate that a considerable number of subjects with high PRS will not demonstrate glaucomatous disease; conversely, some subjects with low PRS will have glaucoma. We will explore whether genetic variants such as MYOC Q368X and unique environmental factors (dietary nitrate intake from vegetable sources, estrogen exposure duration in women and dental health status) modify the relation between our PRS and glaucoma in our 4 study populations. By formulating and applying a multi- ancestral glaucoma PRS to an ethnically-diverse group of subjects, this proposal will highlight the role of a glaucoma genetic informativity panel as a screening tool. This proposal will advance the major objective of promoting POAG to the status of a precision-based medicine discipline. Finally, it will identify specific disease prevention strategies that could be implemented before a diagnosis is made.

原发性开角型青光眼（Primary open-angle glaucoma，POAG）是最常见的青光眼亚型， 具有很强的多基因成分的复杂疾病。该提案与NIH路线图一致， 利用长达十年的POAG基因发现的努力， 促进青光眼的早期诊断，同时概述预防青光眼相关失明的策略。在这 在研究中，我们提出了三个具体目标。1)我们将收集所有发现的POAG常见基因变异， 在过去的十年中，一个多祖先小组在4项独立研究中测试他们是否预测青光眼 人群（英国生物库，一项嵌入基于人群的健康专业病例对照研究） 样本和来自2个医院生物库的患者（总样本量：约600，286例POAG病例中超过12，000例 科目）。2)基于医院的生物库提供了一个机会，以贡献基于精确的医学知识 关于青光眼我们将邀请来自两个医院生物库的800名患有低度和高度青光眼的患者 多基因风险评分（PRS）进行系统的临床评价。这种详细的表型-基因型相关性 将为青光眼提供独特的见解，并将证明这种生物库的实用性，以确定 以前未诊断的疾病，青光眼领域未满足的需求。3)虽然青光眼PRS是 可能是青光眼最强的预测因子，我们预计相当数量的高眼压受试者 PRS不会显示青光眼疾病;相反，一些PRS低的受试者将患有青光眼。 我们将探讨基因变异，如MYOC Q368 X和独特的环境因素（饮食）， 蔬菜来源的硝酸盐摄入量，女性雌激素暴露时间和牙齿健康状况）修改 在我们的4个研究人群中，我们的PRS与青光眼之间的关系。通过制定和应用一个多- 祖先青光眼PRS的受试者的种族多样化的群体，这一建议将突出的作用， 青光眼遗传信息性面板作为筛查工具。该提案将推进以下主要目标： 将POAG提升为精准医学学科。最后，它将确定具体的疾病 可以在诊断之前实施的预防策略。