Inflammasome genes polymorphisms may influence the development of hepatitis C in the Amazonas, Brazil

Abstract

Hepatitis C is considered a major public health problem caused by the hepatitis C virus (HCV). Viral infections are known to induce production of IL1β through the signaling pathway of inflammasomes. Emerging evidences suggest that Inflammasome genes may influence the immune response against HCV as the host genetic background may contribute to the balance between acute and chronic inflammation. We investigated in 151 patients with chronic hepatitis C and 206 healthy blood donors' individuals (HD). Polymorphisms in the IL1B and IL18 genes were genotyped by PCR-RFLP, while NLRP3, CARD8, CTSB and AIM2 by RT- PCR. Serum assay of IL-1β cytokine was performed by ELISA. 84 patients presented mild fibrosis (<F2) and 67 advanced fibrosis (≥ F2). Among the HD individuals the NLRP3-rs10754558 C/C genotype correlated with higher IL-1β levels compared to the G/G genotype. Similar pattern was observed in patients with hepatitis C, mean circulating IL-1β levels were 21,96 ± 4.5 and 10,62 ± 3.3pg/mL among the C/C and G/G genotypes, respectively. This pattern holds even after stratification of the patients into mild fibrosis and advanced fibrosis, demonstrating that the NLRP3-rs10754558 or another polymorphism in linkage disequilibrium with it possibly has an influence on the processing of pro-IL-1β. Notably, higher levels of IL-1β (Mann-Whitney test, p<0.0001) were observed among patients (mean ± SEM: 19,24 ±3.pg/mL) when compared with controls (mean ± SEM: 11,80 ±1.0pg/mL). Gene-gene interaction showed that individuals heterogyzotes for both CARD8-rs2009373 and IL1B-rs16944 are less prone to hepatitis C development (padj = 0.039). Similarly, herozygote carriers for CTSB-rs1692816 and AIM2-rs1103577 (padj = 0.008) or for IL18-rs187238 and NLRP3-rs10754558 (padj = 0.005), have less chances to the development of hepatitis C. However, between subgroups of <F2 and ≥F2, individuals homozygous for the T allele of CARD8-rs2009373 and heterozygous for IL18-rs187238 (padj = 0.028), have mild form of fibrosis.

Fig 1. Serum concentration of IL-1β cytokine in patients with hepatitis C.

Treated (A) and untreated (B), stratified according to the degree of hepatic fibrosis, analyzed as a function of the NLRP3 rs10754558 polymorphisms. Data are expressed as mean ± standard deviation of circulating concentration (pg/mL) of IL-1β cytokine. Statistical analyzes were performed by ANOVA (nonparametric analysis of variance), with Kruskal-Wallis test, followed Dunn’s post-test to compare pairs.