Introduction: The problem of blindness because of glaucoma is increasing due to the aging population. The onset and progression of primary open-angle glaucoma (POAG) is associated with oxidative stress, inflammation, and apoptosis of retinal ganglion cells. Various factors cause increased formation of reactive oxygen species and release of mediators involved in the immune-inflammatory response. Matrix metalloproteinases (MMP) are enzymes involved in the formation of the extracellular matrix in the trabecular meshwork and ciliary body and thus regulate intraocular pressure (IOP). The only proven effective treatment is reduction of IOP. Medication often does not achieve sufficient reduction of IOP, and in some patients the disease progresses despite low IOP. The first prostaglandin analogue latanoprost and selective laser trabeculoplasty (SLT), have been both recommended as the first-choice treatment for POAG by the European Glaucoma Society Guidelines. Currently, there are no clinical or biological markers that would help to predict the risk of POAG, its course or the response to a particular type of treatment.
Hypotheses: Genetic variability may influence the course of POAG. Pharmacogenetic variability predicts response to latanoprost and selective laser trabeculoplasty in patients with POAG and ocular hypertension (OHT). By identifying genetic markers, we can predict which treatment will be more effective and associated with fewer side effects in an individual patient.
Methods: A total of 307 patients with POAG or OHT older than 40 years and 339 controls were included in the study. In the retrospective part, we analyzed common single nucleotide polymorphisms (SNPs) in the genes involved in the pathways of oxidative stress (GSTM1, GSTT1, GSTP1, SOD2, CAT and GPX1), inflammation (TNF, IL1B and IL6) and in the activity of MMP (MMP2, MMP9, MMP14). The prospective part of the study included treatment-naive patients randomized to treatment with latanoprost or SLT, and evaluated the treatment response after 1.5 months. In these patients we also analyzed SNPs in the genes involved in the oxidative and inflammatory pathways, and in MMP genes. In addition, in the latanoprost treatment group, we analyzed SNPs involved in the pharmacodynamics and pharmacokinetics of latanoprost (CES1, CES1P1, BCHE , SLCO2A1, PTGFR).
Results: Homozygotes for GSTM1 gene deletion had a lower risk of developing OHT, while homozygotes for MMP3 rs3025058 had a higher risk of developing OHT. There were more subjects with a higher degree of glaucoma impairment among carriers of at least one GPX1 polymorphic allele, while among carriers of at least one MMP3 polymorphic allele there were more subjects with a lower degree of impairment. The SOD2 rs4880, CAT rs1001179, and TNF 1800629 polymorphisms were associated with an absolute decrease in IOP, whereas carriers of at least one copy of GSTT1 had a lower relative decrease in IOP after latanoprost treatment. IL6 polymorphism was associated with a smaller absolute and relative decrease in IOP after SLT treatment. The clinical-pharmacogenetic model better predicted the effectiveness of IOP reduction (30% and more) in SLT treatment compared to the clinical model, whereas in latanoprost treatment both models had similar predictive value.
Conclusion: SNPs in genes involved in oxidative and inflammatory pathways may be potential biological markers for predicting the risk and progression of POAG, as well as the response to latanoprost and SLT treatment. A clinical-pharmacogenetic prediction model could be helpful in selecting a more effective treatment.
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