The Role of Genetic and Non-Genetic Factors and Causal Mechanisms Underlying Cataract Susceptibility For Risk Prediction

遗传和非遗传因素的作用以及白内障风险预测的因果机制

基本信息

批准号：
10653982
负责人：
Helene Choquet
金额：
$ 40.48万
依托单位：
KAISER FOUNDATION RESEARCH INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-07-01 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10653982
关键词：
Accounting Affect Aging Alcohol consumption Animal Model Behavioral Biological Blindness Body mass index CD100 antigen Candidate Disease Gene Cataract Cataract Extraction Cellular Assay Cigarette Clinical Clinical Data Code Crystalline Lens Data Databases Defect Development Diabetes Mellitus Disease Electronic Health Record Etiology Eye Gene Expression Genes Genetic Genetic Transcription Genotype Glaucoma Goals Histology Homeostasis Hypertension Individual Investigation Knockout Mice Knowledge Lens Opacities Link Literature Medicare Mendelian randomization Meta-Analysis Molecular Myopia Observational Study Operative Surgical Procedures Participant Pathogenesis Pathology Pathway interactions Patients Performance Population Predisposition Prevention Prevention strategy Probability Proteomics Public Health Refractive Errors Regulation Research Risk Risk Factors Role Scanning Electron Microscopy Smoking System Testing Therapeutic Therapeutic Intervention Tissues Variant Vision Visual Acuity Visual impairment age related biobank causal variant cigarette smoking cohort conditional knockout cost disorder risk effective intervention exome sequencing fall injury gene discovery genetic predictors genome wide association study genome-wide genomic locus high body mass index improved innovation insight knockout gene lens mortality mouse model multi-ethnic multiple datasets new therapeutic target non-genetic novel novel strategies personalized intervention polygenic risk score predictive modeling predictive tools prevent programs risk prediction risk prediction model risk stratification risk variant screening tool trait transcriptome transcriptome sequencing

项目摘要

Abstract Age-related cataract, defined as ocular lens opacity, is a leading cause of blindness worldwide. Cataract is also associated with injurious falls and increased mortality and is a significant public health problem in the U.S., accounting for approximately 60% of Medicare costs related to vision. Given the aging U.S. population, cataract surgery demand is expected to double over the next 25 years. Thus, it is important to understand the etiology of cataract to identify at-risk patients and develop effective prevention strategies. Recently, we conducted a large- scale multiethnic genome-wide association study (GWAS) meta-analysis of cataract that has identified 55 genetic loci, including 38 novel loci, that underlie the risk of cataract. Majority of the genes in these loci were independently supported as promising candidates for cataract by the database iSyTE (integrated Systems Tool for Eye gene discovery), based on their significant expression in the lens. While these data uncovered potential new causal genes in the identified loci, their function in the lens is not defined and their role underlying cataract risk remains largely unknown. Further, whether cataract-loci regulate genes and how regulation differs across tissues has not yet been explored. Our study also identified strong genetic correlations between cataract and several disorders/traits, including, glaucoma, myopia, cigarettes smoking, and BMI, supporting previous observational studies. However, it is not clear that these associations are causal. Finally, no predictive tool exists for evaluating individuals at-risk for cataract. The overall objective of this proposal is to understand the role of genetic and non-genetic factors and causal mechanisms underlying the etiology of cataract and develop a prediction tool to facilitate risk-stratified screening for cataract. By leveraging a rich multiethnic cohort, with both genome-wide genotype data and extensive clinical data collected through electronic health records, and using whole-exome sequencing (WES) data of UK Biobank participants, we will accomplish the following specific aims: 1.a) Identify novel genetic predictors of cataract risk using high quality WES data and transcriptome-wide association study (TWAS) approach; 1.b) Evaluate whether glaucoma, myopic refractive error, diabetes, high blood pressure, high BMI, cigarette smoking, or alcohol consumption and other clinical and behavioral factors are causal risk factors of cataract using a Mendelian randomization approach; 2) Develop risk prediction models of cataract risk by integrating polygenic risk scores along with other risk factors; and 3) Determine the function – in the lens using animal models – of novel candidate genes prioritized in cataract-associated loci. This proposed research is significant because it will fill an important gap in cataract genetics and will provide important mechanistic insights into the pathogenesis of cataract. The project is innovative in the development of prediction models of cataract risk based on genetic and non-genetic risk factors as well as the development of novel animal models of cataract. The long-term goal of this research is to advance cataract etiology knowledge for effective interventions and non-surgical therapeutics for its prevention, delay or treatment.

抽象的与年龄相关的白内障，定义为眼镜透明度，是全球失明的主要原因在美国，与伤害性跌倒和死亡率增加有关的重大公共卫生问题约占与视力有关的医疗保险费用的60％。手术需求预计将在未来25年中加倍。白内障目的是确定危险患者并制定有效的预防策略。鉴定全基因组关联研究（GWAS）的白内障荟萃分析已鉴定出55 遗传基因座，包括38个小说基因座，是白内障风险的基础。数据库ISYTE（集成系统工具对于眼基因发现），基于它们在镜头中的显着表达。已确定的基因座中的新因果基因，它们在镜头中的功能不是当之无愧的白内障风险仍然不明尚未探索组织。严重性障碍/特征，包括青光眼，近视，吸烟和BMI，支持以前但是，观察性研究。为了评估人白内障的人的整体目的。遗传和非遗传因素以及因果机制的白内障病因学并发展通过利用丰富的多种组合，可以促进白内障的风险分层筛查的预测工具。全基因组基因型数据和通过电子健康记录收集的广泛临床数据收集器数据，并使用英国生物库参与者的全外观测序（WES）数据，我们将完成以下特定的特定特定目的：1.A）使用高质量的WES数据和整个转录组范围内确定白内障风险的新型遗传预测因子协会研究（TWA）方法； 1.b）评估青光眼，近视误差，糖尿病是否血压，高BMI，吸烟或饮酒以及其他临床和行为因素是使用Mendelian随机方法的白内障的因果风险因素； 2）开发风险预测模型通过整合多基因风险评分以及其他风险因素的风险； 3）在晶状体中，使用动物模型的新型候选基因在白内障相关基因座中优先。研究很重要，因为它将填补白内障遗传学的重要空白，并将提供重要对白内障的发病机理的机械洞察力。基于遗传和非遗传危险因素的白内障风险的预测模型以及发展白内障的新型动物模型。对于有效的干预措施和非手术治疗方法，是预防，延迟或治疗。