Exfoliation syndrome (ES) is a common condition characterized by deposition of a heterogeneous mix of macromolecules throughout the anterior segment of the eye. The factors that cause this material to accumulate in ES remain unknown. ES is a public health problem, because it is a risk factor for high-tension open-angle glaucoma, pre-mature cataract formation, and increased risk of complications during cataract surgery. Previous studies suggest that exfoliation syndrome and the related glaucoma are genetically complex, and one gene, LOXL1, has been identified as a major genetic risk factor. LOXL1 gene variants are found in up to 98% of affected patients;however, these same variants are also present in up to 80% of unaffected individuals, indicating that additional genetic and/or environmental factors are necessary for disease development. Further evidence that LOXL1 is necessary but not sufficient for the disease comes from our preliminary studies of the LOXL1 null mouse that identified some, but not all the phenotypic features of the condition. To identify additional genetic and environmental factors contributing to exfoliation syndrome and exfoliation glaucoma, we have formed a collaborative consortium contributing over 2300 exfoliation cases and 2300 controls. Whole genome genotyping has already been completed in 650 cases and 2250 controls, and over 1000 cases have detailed environmental exposures. We will perform a single stage GWAS to identify additional genetic markers associated with exfoliation syndrome, and will also investigate associations between ES and environmental exposures including factors that influence homocysteine levels the effect of residence in northern latitude. Newly discovered genetic and environmental risk factors will be analyzed for gene- environment and gene-gene interactions.

Public Health Relevance

Exfoliation syndrome is a common condition that causes significant ocular morbidity, and in particular is associated with a severe form of glaucoma. One gene, LOXL1 is known to contribute to this condition, but the high frequency of the LOXL1 risk genotype in normal individuals indicates that other factors are required for disease development. The overall goal of this project is to identify additional factors that contribute to exfoliation, which may be genetic and/or environmental, and may be additive or protective. The identification of new factors can translate into screening tests, and novel strategies for treatment.

National Institute of Health (NIH)
National Eye Institute (NEI)
Research Project (R01)
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Special Emphasis Panel (ZRG1-GGG-C (02))
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Agarwal, Neeraj
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Massachusetts Eye and Ear Infirmary
United States
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Aung, Tin (see original citation for additional authors) (2017) Genetic association study of exfoliation syndrome identifies a protective rare variant at LOXL1 and five new susceptibility loci. Nat Genet 49:993-1004
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Lee, Richard K (2014) New genetic and proteomic discoveries and recent insights into the risk factors and pathophysiology of how pseudoexfoliation glaucoma develops. Preface. Int Ophthalmol Clin 54:vii-viii

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