POLYMORPHISMS OF α1-ANTITRYPSIN AND INTERLEUKIN-6 GENES AND THE PROGRESSION OF HEPATIC CIRRHOSIS IN PATIENTS WITH A HEPATITIS C VIRUS INFECTION
Motawi T, Shaker OG, Hussein RM, Houssen M
*Corresponding Author: Rasha M. Hussein, Ph.D., Department of Biochemistry, Faculty of Pharmacy, Beni-Suef University, Salah Salem Street, 62511, Beni-Suef, Egypt. Tel: +20-12-0013-6515. Fax: +20-82-2317-958. E-mail: rasha.hussein@ pharm.bsu.edu.eg
page: 35

INTRODUCTION

Hepatitis C virus (HCV) infection represents a global health problem, especially in Egypt that showed the highest HCV epidemics worldwide. The national prevalence of HCV infection was recently estimated to be 14.7% [1]. The patients infected with HCV are always at risk of developing progressive liver diseases such as liver cirrhosis and hepatocellular carcinoma [2]. However, it is recognized that some HCV-infected patients do not develop liver cirrhosis during the course of the disease. Such prognostic variation in response to HCV infection suggests that the host genetic factors are involved in the outcome of the disease [3]. Several genetic association studies have implicated different genes such as cytokines to influence the susceptibility or the course of HCV infection [4]. Interleukin-6 (IL-6) is a multifactorial cytokine with a central role in the host immune defense. Recently, over 150 single nucleotide polymorphisms (SNPs) have been discovered at both 3 and 5 flanking regions of the IL-6 gene. These polymorphisms are associated with susceptibility to many different diseases such as idiopathic arthritis and some types of cancer [5]. Specifically, the SNP within the IL-6 promoter region at position 174 (IL-6, rs1800795 is associated with liver cirrhosis and hepatocellular carcinoma [6]. This SNP gives rise to two alleles, G and C, which produce two distinct phenotypes as follows: IL-6 (174 G/G) and IL-6 (174 G/C) genotypes that are called the high producer phenotypes because they are associated with producing higher levels of IL-6 in the blood. The IL-6 (174 C/C) genotype, which is called the low producer phenotype, is associated with producing lower levels of IL-6 [7,8]. α1-Antitrypsin (A1AT) is an acute phase protein produced primarily in the hepatocytes. The blood concentration of A1AT increases three to four times in response to inflammation or tissue injury [9]. Interestingly, A1AT deficiency is associated with chronic liver disease and pulmonary emphysema [10]. So far, over 100 variants have been discovered in the A1AT gene [11]. The wild type M allele is associated with normal concentrations of A1AT in the serum, while the S allele (Glu264Val, rs17580) and Z allele (Glu342Lys, rs28929474) are associated with low concentrations of A1AT and therefore they are known as deficiency variants [12]. Remarkably, the homozygous ZZ genotype is associated with development of liver diseases however, only a few patients with the ZZ genotype eventually develop liver cirrhosis [13]. Importantly, it is widely accepted that IL-6 regulates the expression of acute phase proteins such as A1AT in both hepatic and extra hepatic tissues, where the plasma level of A1AT increases three- to four-fold in response to IL-6 expression [14]. In this study, we aimed to identify the distribution of the SNPs IL-6 174 G/C, rs1800795, S (Glu264Val, rs 17580) and Z (Glu342Lys, rs28929474) mutations at the A1AT gene in Egyptian patients with chronic HCV infection. In addition, we examined the effect of these polymorphisms on the progression of liver cirrhosis.



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