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

基本信息

批准号：
10626069
负责人：
Louis Robert Pasquale
金额：
$ 69.7万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
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/10626069
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&apos Health Study Oral health Papillary Patient-Focused Outcomes Patients Pattern Persons Phenotype Physiologic Intraocular Pressure Population Populations at Risk Prevalence Prevention Prevention strategy Primary Open Angle Glaucoma Probability Progressive Disease Receiver Operating Characteristics Recording of previous events Research Risk Role Sample Size Sampling Screening procedure Site Source Sum Testing Translating United States National Institutes of Health Variant Vegetables Visual Fields Weight Women&apos s Health Work aged biobank clinical phenotype clinically relevant dietary nitrate disorder prevention disorder risk electronic health information endophenotype ethnic diversity feature detection field study gene discovery 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 prediction risk variant screening sex study population tomography tool

项目摘要

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.

原发性开角青光眼（POAG）是最常见的青光眼亚型，是一种典型的常见复杂疾病具有强大的多基因成分。该建议与NIH路线图一致，利用基因发现的十年努力为POAG进行精确医学方法促进早期青光眼诊断，同时概述防止青光眼相关失明的策略。在这个研究，我们提出了3个具体目标。 1）我们将组装所有针对POAG的常见基因变体在过去的十年中，一个多考试面板，以测试它们是否预测4个独立研究的青光眼人口（英国生物银行，一项嵌入基于人群的卫生专业案例对照研究样本，以及来自2个基于医院的生物库的患者（总样本量：超过12,000个POAG病例，〜600,286 主题）。 2）基于医院的生物库为基于精确的医学知识提供了机会关于青光眼。我们将邀请来自两名基于医院的生物库的800名患者用于系统临床评估的多基因风险评分（PRS）。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前未诊断的疾病，是青光眼领域未满足的需求。 3）虽然青光眼PR是可能是青光眼最强的预测指标，我们预计会有大量的受试者 PR不会表现出青光眼疾病。相反，某些PRS低的受试者将患有青光眼。我们将探讨MYOC Q368X和独特的环境因素等遗传变异（饮食蔬菜来源的硝酸盐摄入，女性雌激素暴露持续时间和牙科健康状况）修改在我们的4个研究人群中，我们的PR和青光眼之间的关系。通过制定和应用多个祖先青光眼PR针对一群种族多样性的受试者，该提案将强调青光眼遗传信息面板作为筛查工具。该提议将促进将POAG促进基于精确的药物学科的状况。最后，它将确定特定疾病可以在诊断之前实施的预防策略。

项目成果

期刊论文数量（8）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Genetic Associations Between Smoking- and Glaucoma-Related Traits.

DOI：
10.1167/tvst.12.2.20
发表时间：
2023-02-01
期刊：
TRANSLATIONAL VISION SCIENCE & TECHNOLOGY
影响因子：
3
作者：
Tran, Jessica H;Stuart, Kelsey V;de Vries, Victor;Vergroesen, Joelle E;Cousins, Clara C;Hysi, Pirro G;Do, Ron;Rocheleau, Ghislain;Kang, Jae H;Wiggs, Janey L;MacGregor, Stuart;Khawaja, Anthony P;Mackey, David A;Klaver, Caroline C W;Ramdas, Wishal D;Pasquale, Louis R
通讯作者：
Pasquale, Louis R

Polygenic Risk Score Improves Prediction of Primary Open Angle Glaucoma Onset in the Ocular Hypertension Treatment Study.

多基因风险评分可提高高眼压治疗研究中原发性开角型青光眼发病的预测。

DOI：
10.1101/2023.08.15.23294141
发表时间：
2023
期刊：
medRxiv : the preprint server for health sciences
影响因子：
0
作者：
Singh,RishabhK;Zhao,Yan;Elze,Tobias;Fingert,John;Gordon,Mae;Kass,MichaelA;Luo,Yuyang;Pasquale,LouisR;Scheetz,Todd;Segrè,AyelletV;Wiggs,JaneyL;Zebardast,Nazlee
通讯作者：
Zebardast,Nazlee

Machine Learning-Derived Baseline Visual Field Patterns Predict Future Glaucoma Onset in the Ocular Hypertension Treatment Study.

在高眼压治疗研究中，机器学习衍生的基线视野模式可预测未来青光眼的发病情况。

DOI：
10.1167/iovs.65.2.35
发表时间：
2024
期刊：
Investigative ophthalmology & visual science
影响因子：
4.4
作者：
Singh,RishabhK;Smith,Sophie;Fingert,John;Gordon,Mae;Kass,Michael;Scheetz,Todd;Segrè,AyelletV;Wiggs,Janey;Elze,Tobias;Zebardast,Nazlee
通讯作者：
Zebardast,Nazlee

The Association of Physical Activity with Glaucoma and Related Traits in the UK Biobank.

英国生物库中的体力活动与青光眼及相关特征协会。

DOI：
10.1016/j.ophtha.2023.06.009
发表时间：
2023
期刊：
Ophthalmology
影响因子：
13.7
作者：
Madjedi,KianM;Stuart,KelseyV;Chua,SharonYL;Ramulu,PradeepY;Warwick,Alasdair;Luben,RobertN;Sun,Zihan;Chia,MarkA;Aschard,Hugues;Wiggs,JaneyL;Kang,JaeH;Pasquale,LouisR;Foster,PaulJ;Khawaja,AnthonyP;ModifiableRiskFact
通讯作者：
ModifiableRiskFact

The Association of Female Reproductive Factors with Glaucoma and Related Traits: A Systematic Review.

DOI：
10.1016/j.ogla.2022.06.003
发表时间：
2022-11
期刊：
OPHTHALMOLOGY GLAUCOMA
影响因子：
2.9
作者：
Madjedi, Kian M.;V. Stuart, Kelsey;Chua, Sharon Y. L.;Foster, Paul J.;Strouthidis, Nicholas G.;Luben, Robert N.;Warwick, Alasdair N.;Kang, Jae H.;Wiggs, Janey L.;Pasquale, Louis R.;Khawaja, Anthony P.
通讯作者：
Khawaja, Anthony P.