CYP enzyme polymorphisms and susceptibility to HCV-related chronic liver disease and liver cancer
CYP enzyme polymorphisms and susceptibility to HCV-related chronic liver disease and liver cancer
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DOI：
10.1002/ijc.10937
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发表时间：
2003-04-10
影响因子：
6.4
通讯作者：
Silini, EM
中科院分区：
文献类型：
--
作者：
Silvestri, L;Sonzogni, L;Silini, EM
癌症风险可能受到内源性或环境毒素的影响。参与致癌物代谢活化/解毒的多态性酶可能是个体风险差异的原因。我们研究了P450超家族的五种酶，CYP1A1，CYP1A2，CYP2D6，CYP2E1和CY3A4的多态性，作为丙型肝炎病毒感染患者肝脏疾病进展和癌症的危险因素。通过聚合酶链反应（PCR）限制性片段长度多态性或等位基因特异性PCR进行基因分型。不同阶段的疾病被认为是，如下：90无症状携带者和87慢性肝炎，92肝硬化和91肝细胞癌（HCC）病例。从99名献血员中获得参考等位基因频率。使用卡方（2）检验比较类别间等位基因分布。计算比值比（OR）和95%置信区间（CI）以表示相对风险。通过对应分析和逻辑回归建立独立关联模型。与携带者相比，肝脏疾病患者中CYP1A1高诱导等位基因Msp 1 m2和瓦尔的频率增加;未发现与HCC的特异性关联。与其他HCV类别（包括肝硬化）相比，高活性CYP2E1 c2等位基因在HCC患者中的代表性不足。CYP2D6弱代谢型（PM）基因型在健康受试者（7.1%）和携带者（11.1%）中的频率显著高于肝炎/肝硬化（4.6%）和HCC（1.2%）患者。多变量分析证实了这一点。PM基因型可防止疾病进展，因为OR随分期成比例降低。在非PM个体中，预计诊断HCC的年龄。CYP1A2和CYP3A4基因无差异。HCV基因多态性变异可能导致HCV感染受试者的肝脏疾病进展和HCC风险。(C)2003 Wiley-Liss，Inc.
Cancer risk can be influenced by the exposure to endogenous or environmental toxins. Polymorphic enzymes involved in the metabolic activation/detoxification of carcinogens may account for individual variations of risk. We studied the polymorphisms of five enzymes of the P450 superfamily, CYP1A1, CYP1A2, CYP2D6, CYP2E1 and CY3A4, as risk factors for liver disease progression and cancer in hepatitis C virus-infected patients. CYP genotyping was performed by polymerase chain reaction (PCR) restriction fragment length polymorphism or allele-specific PCR. Different stages of disease were considered, as follows: 90 asymptomatic carriers and 87 chronic hepatitis, 92 cirrhosis and 91 hepatocellular carcinoma (HCC) cases. Reference allele frequencies were obtained from 99 blood donors. Allele distributions among categories were compared using the chi(2) test. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to express relative risks. Independent associations were modeled by correspondence analysis and logistic regression. Frequencies of the CYP1A1 highly inducible alleles, Msp1 m2 and Val, were increased in liver disease patients compared with carriers; no specific association with HCC was found. The high-activity CYP2E1 c2 allele was underrepresented among HCC patients with respect to other HCV categories, including cirrhosis. CYP2D6 poor metabolizer (PM) genotypes were significantly more frequent in healthy subjects (7.1%) and carriers (11.1%) than in hepatitis/cirrhosis (4.6%) and HCC (1.2%) patients. This was confirmed by multivariable analysis. PM genotypes protected against progressive disease as ORs reduced proportionally to stage. The age at diagnosis for HCC was anticipated in non-PM individuals. No differences were seen for CYP1A2 and CYP3A4 genes. Polymorphic variants of CYP genes may contribute to the progression of liver disease and HCC risk in HCV-infected subjects. (C) 2003 Wiley-Liss, Inc.