Identification of Polymorphisms in CYP2E1 Gene and Association Analysis among Chronic HBV Patients

Ji-Yong Chun,Jin-Sol Lee,Jason-Y Kim,Hyun-Sub Cheong,Hyoung-Doo Shin,Byung-Lae Park,Yoon-Jun Kim,Tae-Joon Park,Hyo-Suk Lee

doi:10.5808/gi.2009.7.4.187

Abstract

Abstract Cytochrome P450 2E1 (CYP2E1) is a member of the cy-tochrome P450 superfamily, and it is a key enzyme re-sponsible for the metabolic activation of many small- molecular-weight compounds such as alcohol, which is classified as a human carcinogen. In this study, we identified 19 single nucleotide polymorphisms (SNPs) in CYP2E1 in Korean population. In these SNPs, we exam-ined possible genetic association of CYP2E1 polymor-phisms with HBV clearance and the risk of hepato-cellular carcinoma (HCC). Five common polymorphic sites were selected, CYP2E1 polymorphisms at rs381-3867, rs3813870, rs2070673, rs2515641 and rs2480257, considering their allele frequencies, haplotype-tagging status and LDs for genotyping in larger-scale subjects (n=1,092). Statistical analysis demonstrated that CYP2E1 polymorphisms and haplotypes show no significant as-sociation with HBV clearance, HCC occurrence and on-set age of HCC (p＞0.05). Previous studies, however, have shown contradictory findings on associations of CYP2E1 polymorphisms with CYP2E1 activities and HCC risk. Comparing the contrasting results of previous researches suggest that CYP2E1 polymorphism is asso-ciated with CYP2E1 activity induced by ethanol, but is not directly associated with HCC risk. CYP2E1 varia-tion/haploype information identified in this study will pro-vide valuable information for future studies on CYP2E1.Keywords: cytochrome P450 2E1 (CYP2E1), hepatocell-ular carcinoma (HCC), hepatitis B virus (HBV), chronic hepatitis (CH), liver cirrhosis (LC), polymorphism

Highlights

The infection of hepatitis virus B (HBV) is considered as an important health problem worldwide with an estimation of 350 million people chronically infected with the disease (Lavanchy, 2005)
Hepatic complications do not develop in most chronic hepatitis B carriers, 15% to 40% will develop liver cirrhosis (LC) and hepatocellular carcinoma (HCC), which come with serious sequelae during their lifetime (Bosch et al, 2005)
Cytochrome P450 2E1 (CYP2E1), a member of the cytochrome P450 superfamily is important for the metabolic activation of many low-molecular-weight toxicants such as N-nitrosamines, aniline, vinyl chloride, urethane and alcohol (Guengerich et al, 1991)

Summary

Introduction

The infection of hepatitis virus B (HBV) is considered as an important health problem worldwide with an estimation of 350 million people chronically infected with the disease (Lavanchy, 2005). According to the International Agency for Research on Cancer, ethanol is classified as a human carcinogen because it induces HCC in animals and increases the risk for developing HCC in humans (Baan et al, 2007; Seitz and Stickel 2007). Cytochrome P450 2E1 (CYP2E1), a member of the cytochrome P450 superfamily is important for the metabolic activation of many low-molecular-weight toxicants such as N-nitrosamines, aniline, vinyl chloride, urethane and alcohol (Guengerich et al, 1991). Continuous ethanol consumption is known to increase the activity of CYP2E1 up to 20 fold, a major constituent of the microsomal ethanol oxidizing system in the liver (Stickel & Osterreicher 2006; Takahashi et al, 1993). CYP2E1 often catalyze the metabolic activation of various procarcinogens to eventual carcinogens (Guengerich et al, 1991; Koop, 1992)

Methods

Results

Conclusion