ASSOCIATION OF GENE POLYMORPHISMS OF NOS3 (786T>C), TGFB1 (ARG25PRO) AND EDN (LYS198ASH) WITH THE DEVELOPMENT AND PROGRESSION OF GLOMERULONEPHRITIS OF VARIOUS DEGREE OF ACTIVITY

Relevance. Chronic glomerulonephritis is a multifactorial disease, the pathogenesis of which is significantly influenced by endothelial dysfunction, impaired vasoregulation, and activation of profibrogenic mechanisms. Genetic polymorphisms in the NOS3, TGFβ1, and EDN1 genes, which regulate nitric oxide bioavailability, transforming growth factor β1 activity, and endothelin-1 production, may determine individual predisposition to the progression of renal disease.

The aim of the study was to investigate the role of polymorphic variants of NOS3 786T>C, TGFβ1 Arg25Pro and EDN1 Lys198Asn in the pathogenesis and progression of chronic glomerulonephritis of varying degrees of activity and to assess their association with the severity of the disease.

Materials and methods. Genotyping was performed using the polymerase chain reaction method in the Laboratory of Genome-Cell Technologies of the Institute of Human Immunology and Genomics of the Academy of Sciences of the Republic of Uzbekistan. The distribution of alleles and genotypes of polymorphic variants of TGFβ1 Arg25Pro, NOS3 786T>C (rs2070744), and EDN1 Lys198Asn (rs5370) was studied in patients with varying degrees of glomerulonephritis activity and in the control group. Statistical analysis included the Pearson χ² criterion, Fisher's exact test, odds ratio (OR) estimation with 95% confidence interval, and Hardy–Weinberg equilibrium testing.

Results. In patients with high and very high glomerulonephritis activity, a statistically significant increase in the frequency of the Pro allele of the TGFβ1 Arg25Pro polymorphism was found compared to the control - 11.92% versus 4.17% (OR = 3.11; 95% CI 1.27–7.64; p = 0.012). The frequency of the heterozygous Arg/Pro genotype was also significantly higher - 23.84% versus 8.33% (OR = 3.44; 95% CI 1.38–8.58; p = 0.009). No statistically significant differ­ences in this polymorphism were found in patients with low and moderate disease activity.

For NOS3 786T>C, no statistically significant differences were found in the low and moderate activity groups (p>0.05). At the same time, in patients with high and very high activity, the C allele frequency was 38.74% versus 27.08% in the control group (OR=1.70; 95% CI 1.09–2.65; p=0.018). The most pronounced association was found for the CT genotype, the frequency of which was 64.24% versus 40.28% in the control group (OR=2.66; 95% CI 1.48–4.78; p=0.001).

For the EDN1 Lys198Asn polymorphism, no statistically significant differences in the distribution of alleles and genotypes were found between patients with low/moderate and high/very high disease activity and the control group (p>0.05). These results indicate a possible indirect role of this polymorphism in the development of endothelial dys­function and vascular complications; however, its independent association with glomerulonephritis severity was not confirmed in the study sample.

Conclusion. The most pronounced genetic associations with high chronic glomerulonephritis activity were identified for the TGFβ1 Arg25Pro and NOS3 786T>C polymorphisms. Carriage of the Pro allele of the TGFβ1 gene and the CT genotype of the NOS3 gene are associated with high and very high disease activity, suggesting that these variants may be potential genetic markers for an unfavorable course of glomerulonephritis. The EDN1 Lys198Asn polymorphism did not demonstrate an independent statistically significant association with disease activity, suggest­ing the need for its further evaluation within complex genetic models, taking into account interactions with other regulators of endothelial function.