Influence of transforming growth factor-β1 and tumor necrosis factor-α genes polymorphisms on the development of cirrhosis and hepatocellular carcinoma in chronic hepatitis C patients

Abstract

Background

Host genetic factors may affect clinical outcomes of hepatitis C virus (HCV) infection; however, the possible mechanisms remain largely unknown. This study aimed to evaluate transforming growth factor-β1 (TGF-β1)-509 and tumor necrosis factor-α (TNF-α)-308 genes polymorphisms as a risk factors for cirrhosis and hepatocellular carcinoma (HCC) in chronic hepatitis C patients.

Materials and methods

Two hundred and eighty HCV patients (152 patients with cirrhosis, 128 patients with HCC) and 160 controls were enrolled in the study. Polymorphisms of TGF-β1-509 and TNF-α-308 gene were determined using polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP). Serum TGF-β1 and TNF-α were determined using ELISA.

Results

TGF-β1-509 TT, TNF-α-308 AA and GA genotypes frequencies were significantly increased in cirrhotic and HCC groups. Serum TGF-β1 and TNF-α level were significantly increased in TGF-β1-509 TT and TNF-α-308 AA genotypes respectively.

Conclusion

TGF-β1-509 and TNF-α-308 genes polymorphisms are associated with risk of liver cirrhosis and HCC in patients with chronic HCV infection.

Introduction

Persistent Hepatitis C virus (HCV) infection is widespread; it affects millions of people worldwide [1]. Egypt has the highest countrywide prevalence of HCV in the world; about 12–15% of the total population is infected [2]. Chronic HCV infection causes progressive hepatic fibrosis and cirrhosis in up to 20% of patients and approximately 10–20% of cirrhotic patients may go on to develop hepatocellular carcinoma (HCC) within 5 years [3]. Understanding the risk factors for cirrhosis and/or HCC development in patients infected with HCV is thus of great importance for refinement of treatment strategies and healthcare delivery.

Although the exact mechanism of HCV related hepatocarcinogenesis is still incompletely understood, HCC risk increases with the severity of hepatic inflammation [4], [5]. Chronic inflammation develops through the action of various mediators, which may act as a cofactor in carcinogenesis [6]. Among these mediators, transforming growth factor-β1 (TGF-β1) and tumor necrosis factor-α (TNF-α) play essential roles and have been implicated in inflammation-associated tumors [7].

TGF-β1 is most frequently upregulated in tumor cells. The human TGF-β1 gene is located on chromosome 19q13.1 and the variation among individuals for TGF-β1 production has been considered to be under genetic control [8]. Up to date, several TGF-β1 polymorphisms have been identified. The most studied 509C > T polymorphism is located within an YY1 consensus binding site [9].

TNF-α is a potent pleiotropic proinflammatory cytokine that affects the growth, differentiation, cellular function and survival of all cells. TNF-α is produced by many cell types including macrophages, neutrophils, fibroblasts, keratinocytes, and tumor cells [10]. TNF-α gene is located on the human chromosome 6p21.3 [11]. Several single nucleotide polymorphisms (SNPs) have been identified in the TNF-α promoter region, which are thought to affect TNF-α production [12]. The best documented of these SNPs is at position -308 of the TNF-α gene promoter [13].

Identification of genetic factors related to susceptibility to HCV related cirrhosis and/or HCC would help to elucidate the complex process of cirrhosis and/or hepatocarcinogenesis and improve the scientific basis for preventive interventions. The aim of our study was to assess whether TGF-β1 and TNF-α genes polymorphisms are associated with susceptibility to HCV-related cirrhosis and/or HCC in Egyptian population.