Genetic basis for variation in plasma IL-18 levels in persons with chronic hepatitis C virus and human immunodeficiency virus-1 infections

Abstract

Inflammasomes are multi-protein complexes integrating pathogen-triggered signaling leading to the generation of pro-inflammatory cytokines, including interleukin-18 (IL-18). Hepatitis C virus (HCV) and human immunodeficiency virus-1 (HIV) infections are associated with elevated IL-18, suggesting inflammasome activation. However, there is marked person-to-person variation in the inflammasome response to HCV and HIV. We hypothesized that host genetics may explain this variation. To test this, we analyzed the associations of plasma IL-18 levels and polymorphisms in 10 genes in the inflammasome cascade. 1538 participants with active HIV and/or HCV infection in 3 ancestry groups are included. Samples were genotyped using the Illumina Omni 1-quad and Omni 2.5 arrays. Linear regression analyses were performed to test the association of variants with logIL-18 including HCV and HIV infection status and HIV-RNA, in each ancestry group and then meta-analyzed. Eleven highly correlated SNPs (r2=0.98-1) in the IL18-BCO2 region were significantly associated with logIL-18; Each T allele of rs80011693 confers a decrease of 0.06 log pg/mL of IL-18 after adjusting for covariates (rs80011693; rs111311302 β=-0.06, P-value=2.7×10-4). In conclusion, genetic variation in IL18 is associated with IL-18 production in response to HIV and HCV infection and may explain variability in the inflammatory outcomes of chronic viral infections.

Inflammasomes and their roles in the pathogenesis of viral hepatitis and their related complications: An updated systematic review

“…This issue is complicated with considerable information regarding the association of the polymorphisms within the inflammasomes related molecules with chronic viral hepatitis and their complications. Vergara et al, showed that IL-18 gene polymorphisms are associated with altered serum levels of the cytokine in the HCV infected patients [91]. Association of IL-18 promoter genotype -137 G/G and allele -137 G with decreased serum levels of the cytokine and chronic HBV infectivity, respectively, has been reported by Jiang and colleagues [92].…”

Impact of Sofosbuvir and Daclatasvir therapy on the expression levels of inflammasomes in chronic hepatitis C infected patients

“…IL-18 and IL-1β are important factors contributing to the development of chronic hepatocellular inflammation [11,21,34,35]. Considering that, inflammasome activation is the only described mechanism to convert pro-IL-18 to mature IL-18 [15,19]. So, we focused in our study on IL-18 concentration being a marker of liver inflammation that induced mainly from inflammasomes assembly.…”

“…Inflammasomes are intracellular innate immune sensors, including: NLRP3, AIM2 and IFI16 [14]. They are multi-protein cytosolic complexes that integrate several pathogens triggered signaling cascades, ultimately leading to caspase-1 activation and secretion of pro-inflammatory cytokines including IL-18 and IL-1β [15]. Although, multiple types of inflammasomes were reported to be involved in HCV, others are still unknown and need further investigations [16].…”

“…Inflammasome activation has been the only mechanism described to convert pro-IL-18 to mature IL-18 [14]. Thus, higher levels of IL-18 are considered as an indication of inflammasome activation [15]. IL-18 has been implicated in HCV pathogenesis and correlated with liver injury during HCV infection [14][15][16][17][18][19][20][21].…”

“…Thus, higher levels of IL-18 are considered as an indication of inflammasome activation [15]. IL-18 has been implicated in HCV pathogenesis and correlated with liver injury during HCV infection [14][15][16][17][18][19][20][21]. The continuous stimulation of innate immunity in response to HCV may lead to the progression of liver disease.…”