Document text
Principal Investigator: JAE H KANG
Organization: MASSACHUSETTS EYE AND EAR INFIRMARY
Fiscal Year: 2024
Award: $496,614
Funding agency: National Eye Institute
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.
Terms: <Actinic Rays><Address><Alleles><Allelomorphs><Biological><Blindness><Blood Plasma><Cataract><Cataract Extraction><Causality><Cephalins><Cholesterol><Clinical><Coffee><Collaborations><Complex><Consumption><Cortisone><Data><Development><Diagnosis><Diagnostic><Disease><Disorder><Ear><Environmental Exposure><Environmental Factor><Environmental Risk Factor><Epidemiology><Ethanolamine Phosphoglycerides><Ethanolamineglycerophospholipids><Etiology><Event><Exfoliation Syndrome><Exfoliative Syndrome><Eye><Eyeball><Folate><Folic Acid><Follow-Up Studies><Followup Studies><Frequencies><Funding><GWA study><GWAS><Gene Expression><Genetic><Genetic Risk><Genetic predisposing factor><Genomics><Genotype><Glaucoma><Glaucoma Capsulare><Goals><Haplotypes><Health Care Professional><Health Professional><Healthcare professional><Individual><Intake><International><Lipids><Lysolecithins><Lysophosphatidylcholines><Maps><Measures><Mediating><Mediation><Mediator><Mendelian randomization><Meta-Analysis><Metabolite Interaction><Molecular><Morbidity><Morbidity - disease rate><Negotiating><Negotiation><Nurses' Health Study><O-(1-beta-acyl-2-acyl-sn-glycero-3-phospho)-ethanolamine><Onset of illness><Participant><Pathogenesis><Pathogenicity><Pathway interactions><Patients><Phosphatidylethanolamine><Plasma><Plasma Serum><Plasmalogens><Preventative strategy><Prevention strategy><Prevention therapy><Preventive strategy><Primary Prevention><Pseudo-Exfoliation Syndrome><Pseudoexfoliation Syndrome><Pteroylglutamic Acid><Public Health Practice><Reticuloendothelial System, Serum, Plasma><Risk><Risk Factors><Risk-associated variant><SEQ-AN><Sampling><Sampling Studies><Sequence Analyses><Sequence Analysis><Steroid Compound><Steroids><Time><Triacylglycerol><Triglycerides><UV light><UV radiation><UV rays><Ultraviolet Rays><Variant><Variation><Vitamin M><Work><biobank><biologic><biorepository><case control><case-controlled><cataract surgery><cataractogenesis><cataractous lenses><causation><clinical relevance><clinically relevant><cost><curative intervention><curative therapeutic><curative therapy><curative treatments><developmental><disease causation><disease onset><disorder onset><environmental risk><epidemiologic><epidemiological><exome><exomes><gene locus><genetic locus><genetic risk factor><genome wide association><genome wide association scan><genome wide association studies><genome wide association study><genomewide association scan><genomewide association studies><genomewide association study><genomic location><genomic locus><glaucomatous><inherited factor><insoluble aggregate><lipid mediator><meeting><meetings><metabolism measurement><metabolomics><metabonomics><multidisciplinary><new drug target><new drug treatments><new druggable target><new drugs><new pharmacological therapeutic><new pharmacotherapy target><new therapeutic target><new therapeutics><new therapy><new therapy target><next generation therapeutics><novel><novel drug target><novel drug treatments><novel druggable target><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel pharmacotherapy target><novel therapeutic target><novel therapeutics><novel therapy><novel therapy target><pathway><polygenic risk score><premature><prematurity><prospective><protective effect><protein aggregate><protein aggregation><residence><residential building><residential site><risk allele><risk gene><risk genotype><risk loci><risk locus><risk variant><screening><screenings><ultra violet light><ultra violet radiation><ultra violet rays><ultraviolet light><ultraviolet radiation><vision loss><visual loss><vitamin Bc><whole genome association analysis><whole genome association studies><whole genome association study>