微粒体环氧化物水解酶多态性和单倍型作为印度人群中乙型肝炎病毒和丙型肝炎病毒相关肝病的决定因素
Microsomal Epoxide Hydrolase Polymorphisms and Haplotypes as Determinants of Hepatitis B Virusand Hepatitis C Virus-related Liver Disease in Indian Population.
作者信息
Rahat Beenish, Kiran Manjula, Saxena Roli, Chawla Yogesh K, Sharma Rati R, Kaur Jyotdeep
机构信息
Department of Biochemistry, Postgraduate Institute of Medical Education and Research, Chandigarh - 160012, India.
Department of Hepatology, Postgraduate Institute of Medical Education and Research, Chandigarh - 160012, India.
出版信息
J Clin Exp Hepatol. 2012 Jun;2(2):104-11. doi: 10.1016/S0973-6883(12)60097-8. Epub 2012 Jul 21.
BACKGROUND
Hepatocellular carcinoma (HCC) is the fifth most common cancer and third leading cause of death worldwide. Main causes of HCC are hepatitis B virus (HBV) and hepatitis C virus (HCV) infections. mEPHX, a xenobiotic metabolizing enzyme, exhibits a dual role of procarcinogen detoxification and activation, hence considered as a cancer risk factor as well as a protective factor. Two known polymorphic forms of mEPHX, exon in exon 3 and 4, are associated with the development of HCC.
OBJECTIVE
To determine the association of genotypes and haplotypes of mEPHX with risk of HCC developments separately in HBV- and HCV-infected carriers and patients with hepatitis.
METHODS
Polymerase chain reactions (PCR) were carried out using primers to amplify exon 3 (113 Tyr→His variant) and exon 4 (139 His→Arg) polymorphic sites. To distinguish the wild and variant forms, PCR amplification products were digested with restriction endonucleases EcoRV and Rsa1 for exons 3 and 4, respectively.
RESULT
Exon 3 genotypes, Y113H and H113H, shared a protective association with HBV-chronic hepatitis infection (P < 0.001 and P< 0.01, respectively) as well as HBV-HCC development (P < 0.001) among HBV-carrier group, while Y113H acts as a risk factor for HCV-chronic hepatitis development (P < 0.001) as well as for HCC development (P < 0.01) with HCV-carrier group as reference. Both H139R and R139R, exon 4 genotypes, acted as a risk factor for HBV/HCV-chronic hepatitis infection and for HBV/HCV-HCC development (P ranges from < 0.05 to < 0.001) with HBV/HCV carriers as reference. 113His-139His and 113His-139Arg haplotypes shared a significant negative and positive association, respectively, with HBV hepatitis and HBV-HCC risk. 113Tyr-139Arg haplotype acted as a risk for HCV-HCC development.
CONCLUSION
Polymorphic and haplotypic variant forms of mEPHX exon 3 and 4 variably determine the susceptibility to develop HCC in HBV- and HCV-carrier subjects.
背景
肝细胞癌（HCC）是全球第五大常见癌症和第三大死亡原因。HCC的主要病因是乙型肝炎病毒（HBV）和丙型肝炎病毒（HCV）感染。mEPHX是一种外源性代谢酶，具有前致癌物解毒和激活的双重作用，因此被认为是一种癌症风险因素以及保护因素。mEPHX的两种已知多态性形式，即外显子3和4中的外显子，与HCC的发生发展相关。
目的
分别确定mEPHX的基因型和单倍型与HBV和HCV感染携带者及肝炎患者发生HCC风险的关联。
方法
使用引物进行聚合酶链反应（PCR），以扩增外显子3（113 Tyr→His变异）和外显子4（139 His→Arg）多态性位点。为区分野生型和变异型，分别用限制性内切酶EcoRV和Rsa1对PCR扩增产物进行外显子3和4的酶切。
结果
在外显子3基因型中，Y113H和H113H与HBV携带者组中的HBV慢性肝炎感染（分别为P < 0.001和P < 0.01）以及HBV-HCC发生（P < 0.001）均存在保护性关联，而以HCV携带者组为参照，Y113H是HCV慢性肝炎发生（P < 0.001）以及HCC发生（P < 0.01）的风险因素。外显子4基因型H139R和R139R均是以HBV/HCV携带者为参照的HBV/HCV慢性肝炎感染以及HBV/HCV-HCC发生的风险因素（P范围为< 0.05至< 0.001）。113His-139His和113His-139Arg单倍型分别与HBV肝炎和HBV-HCC风险存在显著的负相关和正相关。113Tyr-139Arg单倍型是HCV-HCC发生的风险因素。
结论
mEPHX外显子3和4的多态性和单倍型变异形式可不同程度地决定HBV和HCV携带者发生HCC的易感性。
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