# Genetic and Environmental Risk Factors for Exfoliation Syndrome and Glaucoma

> **NIH NIH R01** · MASSACHUSETTS EYE AND EAR INFIRMARY · 2022 · $566,634

## Abstract

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.

## Key facts

- **NIH application ID:** 10467732
- **Project number:** 2R01EY020928-10
- **Recipient organization:** MASSACHUSETTS EYE AND EAR INFIRMARY
- **Principal Investigator:** JAE H KANG
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $566,634
- **Award type:** 2
- **Project period:** 2011-09-01 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10467732

## Citation

> US National Institutes of Health, RePORTER application 10467732, Genetic and Environmental Risk Factors for Exfoliation Syndrome and Glaucoma (2R01EY020928-10). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10467732. Licensed CC0.

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