Avaliação dos polimorfismos em genes de citocinas e do inflamassoma no desenvolvimento da fibrose hepática em pacientes com hepatite C

Abstract

Hepatitis C is an inflammatory disease of the liver caused by the hepatitis C virus (HCV). Differences in the prognosis of infected individuals are observed, among which, in turn, 70% present chronic hepatitis C and may develop hepatic fibrosis, cirrhosis and hepatocellular carcinoma. The clinical manifestations and the evolution of the disease are related to the way the immune system interacts and responds against HCV. A successful immune response is essential for virus elimination, however, host genetic characteristics may result in immune responses with gain or loss of function changes, which may be associated with chronic inflammation and persistent infection. Viral infections are known to induce production of IL-1β through the signaling pathway of inflammasomes. The IL-1β cytokine would act on the antiviral response by inducing proinflammatory genes via activation of NF-κB by recruiting leukocytes to the site of infection and modulating the action of infiltrated cells. On the other hand, IL-1β could also promote the production of pro-fibrogenic molecules, contributing to the development of diseases related to HCV. Objective: To evaluate the polymorphisms in the IL-1β and IL-18 cytokine genes and the inflammasomes NLRP3, CARD8, CTSB and AIM2 in the development of hepatic fibrosis in patients with hepatitis C, attended at a reference unit in the Brazilian Amazon. Polymorphisms in the IL-1β and IL-18 genes were genotyped by PCR-RFLP, while NLRP3, CARD8, CTSB and AIM2 by Real-Time PCR. Serum quantification of IL-1β cytokine was performed by the ELISA technique. Results: In the present study we analyzed 151 samples from patients with chronic hepatitis C and 206 samples from the control group. Among the patients, 84 presented mild fibrosis (<F2) and 67 advanced fibrosis (≥ F2). Gene interaction was observed between CARD8 rs2009373 C/T and IL1β rs16944 C/T (padj = 0.039), as well as for CTSB rs1692816 A/C and AIM2 rs1103577 C/T (padj = 0.008), suggesting that there is cooperation between these SNPs in protection against the development of hepatitis C. In the analysis of gene interaction between the subgroups of patients with hepatitis C (<F2 vs ≥F2), a interaction was observed between CARD8 rs2009373 T/T and IL18 rs187238 G/C (padj = 0.028), suggesting that there is cooperation between these SNPs in protection against the development of hepatic fibrosis. Conclusion: In this study, we described the allelic and genotype frequencies for the polymorphisms in the studied genes, in addition to observing that there seems to be cooperation between some genes, which encode components of inflammasomes, in order to provide protection against HCV infection and development of liver fibrosis.