Glaucoma is a common cause of blindness, which affects approximately 60 million people worldwide. Pseudoexfoliation (PXF) syndrome is currently the single most important identifiable cause for developing open angle glaucoma (PXFG). It is an age related generalized disorder of the extracellular matrix characterised by the production and progressive accumulation of fibrillar material in ocular tissue. PXF syndrome is a complex, multifactorial disease involving a combination of both genetic and non-genetic factors in its pathogenesis. Single nucleotide polymorphisms (SNPs) in the lysyl oxidase-like 1 (LOXL1) gene have been identified as a major genetic risk factor for PXF syndrome and glaucoma. This strong association has been uniformly replicated in all geographic populations studied to date, conferring an approximately 20-fold risk for disease. Surprisingly they also occur in 50-80% of the normal population indicating that many other factors must contribute to disease pathogenesis and progression. Possible contributory factors may include oxidative stress and hypoxia as well as high levels of pro-fibrotic growth factors and cytokines such as transforming growth factor beta 1(TGFbeta1). Given that tissue hypoxia present in glaucoma can alter the human genome through addition of epigenetic modifications such as methylation, we hypothesize that LOXL1 may be epigenetically modified in glaucoma as previously reported in other diseases. The aim of this study is to investigate the role of epigenetics in the regulation of LOXL1 (& TGFbeta1) in PXFG patients, specifically in human tenon fibroblasts and anterior lens capsules by promoter methylation analysis, chromatin immunoprecipiation assays and inhibitor studies. We will also perform LOXL1 genotyping (SNP analysis) and relate clinical and laboratory findings which will be faciliated by a specialized study database.
It is the long-term aim of this project to explore ways of pharmacologically reversing these epigenetic abnormalities by use of chromatin modifying intervention for therapeutic benefits.
