Genetic variants in IL-6 and IL-10 genes and susceptibility to hepatocellular carcinoma in HCV infected patients

Highlights

• IL-10 rs1800871, rs1800872, and rs1878672 variants were associated with HCV outcome.

• High IL-6 levels in HCV infected patients are associated with disease progression.

• IL-6 rs1800796 variant was associated with hepatocellular carcinoma.

• IL-10 and IL-6 SNPs markedly influence the clinical outcomes of HCV infection.

Abstract

Background

Hepatitis C virus (HCV) infection is the major cause of hepatocellular carcinoma (HCC), a common primary liver malignancy, and the third leading cause of cancer-related death. The HCC risk increases with the severity of liver inflammation, and the clinical course of HCV infection depends on a balance between pro- and anti-inflammatory cytokines. The former includes interleukin (IL)-6, while the latter includes IL-10. However, the exact pathogenic mechanisms underlying IL-6 and IL-10 effects remain unclear.

Methods

The present study evaluated 174 chronic HCV Tunisian patients. Polymorphisms of IL-6 (rs1880242, rs1474847, rs2069840, rs1800797, rs1800796, rs2069845, rs2069827, rs1474348, rs1800795), and IL-10 (rs1800896, rs1800871, rs1800872, rs1554286, rs1878672, rs1518111) were determined by real-time PCR.

Results

Notable differences between chronic HCV-infected patients and HCC patients were observed for the three IL-10 SNPs; rs1800871 (−819T/C), rs1800872 (−592A/C), and rs1878672. Carriage of IL-6 rs1800796 G/G genotype, IL-6 rs1474358 C-allele, and IL-6 rs1800797 A-allele was more frequent in chronic HCV-infected patients than in HCC patients. On the other hand, IL-6 rs1474358 GG genotype had a favourable factor for HCC establishment.

Conclusion

IL-10 and IL-6 SNPs markedly influence the clinical outcomes of HCV infection. These SNPs could be used as biomarkers for early detection and molecular therapy for preventing HCC, and prognostic factors for predicting the clinical outcomes of HCC.

Introduction

The incidence of HCV and related complications continue to rise globally, and World Health Organization (WHO) reporting an estimated 3% prevalence worldwide [1], [2]. Hepatocellular carcinoma (HCC) is the primary liver malignancy, and the third leading cause of cancer-related deaths worldwide [2]. Chronic HCV infection is associated with variable outcome, ranging from simple hepatic damage, to cirrhosis, and HCC [3]. Most HCV-related HCC cases are found in developing countries [4], and the progression and the development of HCC correlates with HCV infection, predominantly in cirrhosis. Accordingly, routine examination and assessment, including HCV genotype and viral load, will improve the prognosis of HCV infection.

The course of HCV infection is influenced by modifiable and non-modifiable factors, such as duration of infection, gender, alcohol consumption, age, and insulin resistance [5]. Despite the identification of these and related factors, the exact cause underlying most HCV infection cases remain unexplained, suggesting the contribution of other factors, in particular the immune status of the host. A large numbers of single nucleotide polymorphisms (SNPs) in both pro- and anti-inflammatory cytokine genes were previously associated with the outcome of chronic HCV infection [6], including interleukin (IL)-6, a pleiotropic cytokine with a key role in inflammation [7], and innate adaptive immunity [8]. As carcinogenesis is accompanied by a state of low-grade inflammation, a key role for altered IL-6 signalling in human cancers were reported previous reports linking [9], [10], [11].

Recently, IL-6 was shown to drive the differentiation on naïve Th0 cells to the Th17 cell lineage [12], [13]. This expands the role of IL-6, from involvement in innate immunity to its significant contribution to chronic inflammation accompanying disease process. IL-6 is a pleiotropic cytokine expressed by many cell types, and regulates several inflammatory processes, haematopoiesis and immune regulation. Dysregulated IL-6 expression was often seen in cancer, and a role for IL-6 as a prognostic biomarker for breast and prostate cancer was suggested [14]. Elevation in IL-6 serum levels correlated with advanced stages of cancer, and was linked with poor prognosis. The pleiotropy and redundant functions of IL-6 underscores an important signalling axis in oncogenic transformations.

On the other hand, IL-10 is an anti-inflammatory cytokine, which downregulates the synthesis of pro-inflammatory cytokines, including IL-6, and modulates hepatic fibrogenesis [15]. Several study addressed the possible contribution of IL-10 promoter polymorphisms to HCV outcomes. IL-10 plays a key role in the oncogenic and metastatic ability of neoplasms [16], exemplified by the reported increases in IL-10 levels in cancer patients, including those with HCC [17], [18], where it was related to the disease prognosis. Several cell types, including T cells, B cells, monocytes, macrophages, mast cells, granulocytes, dendritic cells and keratinocytes, produce IL-10. Tumor cells and tumor-infiltrating macrophages are also major IL-10 secreting cells [19], [20]. IL-10 exerts immunosuppressive effect on antigen presentation, cell maturation and differentiation, thereby allowing evasion of tumor cells of immune recognition [21]. This indicates that IL-6 and IL-10 drive tumor progression by dampening anti-tumor immunity, and by precipitating by state of inflammation, and escape of apoptotic processes.

The aim of this study was to determine whether specific IL-10 genotypes influence the outcomes of HCV infection in Tunisian patients. The second objective was to examine the possible association of IL-6 promoter polymorphisms with the outcomes of chronic HCV infection.