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.

A preliminary study on the association between pro-inflammatory cytokine IL-1 beta polymorphisms and susceptibility to hepatitis C infection in Malay male Malay drug abusers

“…However, the genotypes associated with HCV infection susceptibility are diverse. While one study found that the C/C genotype was predominant in HCV-positive patients 42 , another reported that the C/T genotype was more prevalent in Wang et al's study (2003) 43 . Moreover, other research has concluded that the T/T genotype was a significant risk factor for the progression of chronic HCV infection to HCC 44 .…”

“…Moreover, other research has concluded that the T/T genotype was a significant risk factor for the progression of chronic HCV infection to HCC 44 . In addition, the mutant T/T allele has been frequently reported in patients with chronic HCV and HCV-induced liver cirrhosis 42 . An extensive inflammasome gene polymorphism study reported that the C allele of IL-1β rs16944 was less likely to advance hepatitis C development 45 .…”

Predictive Power of Tissue and Circulating Biomarkers for the Severity of Biopsy-Validated Chronic Liver Diseases

“…Purinergic receptors have been associated with HCV; thus, P2X4R regulates the secretion of micro-RNA containing exosomes by HCV-infected hepatocytes [ 18 ], and polymorphisms of genes encoding for inflammasome components, including AIM2, have been correlated to the development of C-hepatitis in Amazonia [ 19 ]. Higher expression levels of such molecules are found in blood samples of HCV patients compared to healthy blood donors’ individuals, with a positive association with the disease stage.…”

Influência de polimorfismos no gene MTTP nos níveis de lipídeos e na esteatose associada à infecção crônica pelo vírus da hepatite C

“…No presente estudo não foi encontrada associação significativa, após a análise multivariada, dos SNPs Q95H e Q244E com a esteatose hepática nos HCV (Cai et al, 2011;Coppola et al, 2015a;Eslam et al, 2016;Fan et al, 2016, Kralj et al, 2016. Além disso, estudos que avaliam os efeitos combinados entre polimorfismos na infecção pelo HCV têm se mostrado relevantes (Gao et al, 2017;Huang et al, 2017;Toro et al, 2021;Tao et al, 2022), uma vez que os polimorfismos podem contribuir para o desenvolvimento de doenças e comorbidades e alguns podem não ter funções independentes. Tao et al (2022), por exemplo, descreveram que polimorfismos nos genes Transporter associated with antigen processing (TAP) e HLA-I podem apresentar um efeito combinado na suscetibilidade à hepatite C crônica (Tao et al, 2022).…”