Genetic and Environmental Risk Factors for Exfoliation Syndrome and Glaucoma

剥脱性综合征和青光眼的遗传和环境风险因素

• 批准号: 10467732
• 负责人: JAE H KANG
• 金额: $ 56.66万
• 依托单位: MASSACHUSETTS EYE AND EAR INFIRMARY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10467732
• 关键词: Address; Alleles; Biological; Blindness; Cataract; Cataract Extraction; Cholesterol; Clinical; Coffee; Collaborations; Complex; Consumption; Cortisone; Data; Development; Diagnosis; Diagnostic; Disease; Ear; Environmental Exposure; Environmental Risk Factor; Epidemiology; Etiology; Event; Exfoliation Syndrome; Eye; Folic Acid; Follow-Up Studies; Frequencies; Funding; Gene Expression; Genetic; Genetic Risk; Genomics; Genotype; Glaucoma; Goals; Haplotypes; Health Professional; Individual; Intake; International; Lipids; Lysophosphatidylcholines; Maps; Measures; Mediating; Mediation; Mediator of activation protein; Mendelian randomization; Meta-Analysis; Metabolite Interaction; Molecular; Morbidity - disease rate; Nurses' Health Study; Onset of illness; Participant; Pathogenesis; Pathogenicity; Pathway interactions; Patients; Phosphatidylethanolamine; Plasma; Plasmalogens; Prevention strategy; Prevention therapy; Primary Prevention; Public Health Practice; Risk; Risk Factors; Sampling; Sampling Studies; Sequence Analysis; Steroids; Time; Triglycerides; Ultraviolet Rays; Variant; Work; biobank; case control; clinically relevant; cost; curative treatments; exome; genetic risk factor; genome wide association study; genomic locus; lipid mediator; meetings; metabolomics; multidisciplinary; new therapeutic target; novel; novel therapeutics; polygenic risk score; premature; prospective; protective effect; protein aggregation; residence; risk variant; screening

Exfoliation syndrome (XFS) is a common systemic disorder characterized by progressive accumulation of abnormal fibrillar protein aggregates and that is associated with glaucoma (XFG), pre-mature cataract formation, and complications during cataract surgery as well as several systemic conditions. Our goal is to elucidate the pathogenesis of exfoliation syndrome (XFS) and the associated glaucoma (XFG), which will facilitate effective screening and prevention strategies and the development of novel therapies. Aggregated LOXL1 is one component of the pathogenic fibrillar aggregates, and LOXL1 is a major genetic risk factor for XFS/XFG, with LOXL1 risk variants occurring in up to 98% of patients. However, XFS/XFG is genetically complex, and these same common risk variants are also present in many unaffected individuals, indicating that additional genetic and/or environmental factors are necessary for disease development. During the previous funding period we have made significant progress defining environmental exposures influencing XFS/XFG risk including time spent outdoors, residential latitude, UV light exposure, heavy coffee consumption and low folate intake. In collaboration with our international consortium, we have identified new genetic factors influencing risk including protective LOXL1 variants. We have also completed a metabolomics study using pre-diagnostic samples from the longitudinal Nurses’ Health Study (NHS) and Health Professionals Follow-up Study (HPFS) that identified 2 plasma metabolites classes (lysophosphatidylcholines and phosphatidylethanolamine plasmalogens), measured as much as a decade before disease onset, associated with increased XFS/XFG risk, and the individual metabolite cortisone and the metabolite classes of steroids and triglycerides inversely associated with risk. For the next funding period, we will build on these results using data from the NHS, NHS2 and HPFS, Mass Eye and Ear clinical case control set, and UK Biobank, to further define the complex set of risk factors contributing to this important blinding disease. We propose the following specific aims: 1) Investigate associations between steroids, lipid metabolites, environmental factors and XFS/XFG risk; 2) Investigate the contributions of rare/low frequency LOXL1 variants to XFS/XFG risk and 3) Evaluate integrated metabolomic and genomic effects on XFS/XFG risk. This unique study with comprehensive prospective environmental, genetic and metabolomic data and a multi-disciplinary team (expertise in genetics, metabolomics, epidemiology) will cost-efficiently address a significant cause of ocular morbidity. The findings will be directly relevant for clinical and public health practice.

剥落综合征（XFS）是一种常见的全身性疾病，其特征是皮肤的渐进性积累