Pseudoexfoliation glaucoma – Do genes or environment matter more?

Abstract

AbstractPurposeLysyl oxidase like 1 (LOXL1) catalyzes collagen and elastin crosslinking. Single nucleotide polymorphisms (SNPs) within LOXL1 are associated with pseudoexfoliation (PXF) syndrome and PXF glaucoma (PXFG). These SNPs are present in 50%–80% of the general population, suggesting environmental factors also play a role in disease development. Our aim was to investigate LOXL1 levels in Human Tenons Fibroblasts (HTFs) and aqueous humour (AqH) from PXF, PXFG and cataract controls (CAT) and to establish if there was an association with genotype, epigenetic regulation (methylation) or environmental factors (hypoxia, oxidative stress, UV exposure and caffeine intake).MethodsPatients with PXF, PXFG and CAT were recruited and genotyped. LOXL1 expression was measured by qPCR and Western Blot and LOXL1 activity by ELISA. CAT HTFs were cultured in hypoxic (1% O2) and oxidative stress conditions (200 μm hydrogen peroxide). Epigenetic analysis was determined by global DNA methylation and qPCR of methylation‐associated enzymes. Environmental factors were recorded in a RedCap™ database.ResultsIncreased high‐risk LOXL1 gene haplotypes were observed in PXFG compared with CAT. LOXL1 expression and activity was decreased in PXFG HTFs vresus CAT (p < 0.01). This was replicated in CAT HTFs cultured under hypoxic (p < 0.05) and oxidative stress conditions (p < 0.01). Global DNA methylation and DNMT1 and 3A expression was increased in PXFG compared to CAT (p < 0.05). DNMT inhibition using 5‐azacytidine restored LOXL1 expression in PXFG (p < 0.05). Outdoor occupation was associated with PXFG. PXFG patients with the high‐risk (G‐G) haplotype had higher rates of trabeculectomy and numbers of IOP lowering drugs.ConclusionsA combination of genetic, epigenetic and environmental factors contributes to LOXL1 expression in PXFG. LOXL1 genotyping may offer a means of screening for risk of disease progression and epigenetic modifiers such as 5‐azacytidine may represent a future therapeutic target for PXFG.