The dissertation is devoted to solving the urgent problem of modern ophthalmology – improvement of early diagnosis of development and prediction of complications in patients with primary open-angle glaucoma (POAG) on the basis of a comprehensive clinical, ophthalmological and molecular genetic study of genetic single nucleotide variation (SNV) rs1799983 and rs2070744 of endothelial NO-syntase gene (NOS3).
The scientific novelty of the obtained results.
According to the results of this study, the vast majority of surveyed patients had stage III POAG (52.94%), approximately the same number of patients were with other stages: 11.76% – with stage I; 17.65% with stages II and IV. A statistically significant increase in the duration of the disease was noted according to the stages of PVCG: from 1 year (95% CI 0.60 – 1.36) with stage I POAG to 5.9 years (95% CI 4.15 – 7.62) with IV ( p<0.001). All ophthalmological indicators naturally worsened from I to IV stage (p<0.001).
According to ROC analysis, the ratio of the area of excavation to the area of the optic nerve disc (Cup/Disk Area Ratio) had the greatest predictive power for the diagnosis of a certain stage of POAG - AUC=0.904 (95% CI 0.830 - 0.953; p<0.001), which allowed us to consider this the indicator is the most sensitive (Se=95.56%) and specific (Sр=100.0%) for the diagnosis of PVCG of all stages.
For the first time, data on the distribution of the studied genetic SNV in patients on POAG from the Ukrainian population of the Dnipropetrovsk region were obtained. The presence of the TT and allele T SNV rs1799983 (G894T, Glu298Asp) genotype of the NOS3 gene was a risk factor for POAG (OR=1.806; 95% CI 1.11-2.93; p 0.016). Carriers of the TT genotype had a 3.3-fold higher risk (p<0.001) of POAG than carriers of other genotypes (GG+GT).
Stratification by sex showed that the association with POAG was maintained in women with the risk T allele (OR=2.00; 95% CI 1.01-3.95; p=0.043).
It was found that due to the risk TT genotype and T allele rs1799983, POAG developed at a younger age, such individuals had higher internal pressure, worse perimetry (MD and PSD), less thickness of the retinal nerve fibers (RNFL) and ganglionic macula cells (GCC), greater ratio of excavation area to optic disc area (Cup/Disk Area Ratio).
Installed for the first time that the rs2070744 allelic SNV of the NOS3 gene had a protective effect against the development of POAG (for the T allele: OR=0.589; 95% CI 0.370-0.938; p=0.025). T allele carriers had better perimetry (MD and PSD) and greater thickness of the retinal nerve fibers (RNFL) and macular ganglion cell complex (GCC).
Genetic predisposition to the development of POAG in carriers of the ancestral C allele rs2070744 (OR=1.699; 95% CI 1.066-2.706; p=0.025), in which the disease developed at a young age and was accompanied by rapid development, worse perimetry and more pronounced dystrophy of the layers in comparison with carriers of other genotypes.
Expanded knowledge: it was shown that ophthalmic parameters depended on the genotypes of both polymorphisms during stratification by POAG stages – the worst indicators were determined for carriers of TT rs1799983 and CC rs2070744 genotypes, which was preserved for III and IV stages.
For the first time, it was established that carriers of a combination genotypes rs1799983-rs2070744 GT-CC and TT-CC had a significantly increased risk of POAG: OR=4.39 (95% CI 1.00-19.30; p=0.048) and OR=14.15 (95 % CI 1.88-106.28; p<0.001), respectively. The rate of POAG progression was higher in carriers of a combination genotypes: TT-CC, GT-CC and GT-CT. For each of these combination genotypes, the rate of progression of POAG was higher in women than in men.
The practical significance of the obtained results.
The presence of risk genotypes SNV rs1799983 and rs2070744 of the NOS3 gene must be taken into account when examining patients with POAG. Taking into account their presence and gender, an ordinal regression model of the rate of progression of the disease burden of POAG was built with satisfactory prognosis indicators (AUC=0.953; 95% CI 0.912 - 0.979; p<0.001).
The calculation of the "hereditary" age of patients, in which one or another stage of POAG should be expected, was calculated. In the presence of one of the risk alleles (combination genotypes GG-CT, GT-TT, GG-CC) the age of onset of POAG decreased (up to 22-39 years), but the age of development of stages III and IV was predicted to be very high (over 84 years). In the presence of two risk alleles, both the age of onset and the age of development of high-grade POAG significantly decreased, which was especially characteristic of carriers of the TT-CC combination genotypes
