CYP enzyme polymorphisms and susceptibility to HCV‐related chronic liver disease and liver cancer

Abstract

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 virusinfected 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 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, MspI 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. © 2003 Wiley-Liss, Inc. Key words: drug-metabolizing enzymes; DNA polymorphism; chronic liver disease; genetic susceptibility Hepatocellular carcinoma (HCC) ranks fifth among causes of cancer mortality worldwide and is responsible for approximately 1 million deaths yearly. 1 HCC almost invariably arises in the setting of chronic progressive liver diseases, in particular, chronic infections by hepatitis B and C viruses. 2,3 Hepatitis C virus (HCV) infection is presently the major cause of chronic liver disease in the West, and it is associated with over 80% of HCC cases in Italy, 4 where there are an estimated 2 million HCV-infected patients. 5 In about 20% of patients, chronic hepatitis C progresses to cirrhosis, 6 which is complicated by HCC development at a yearly rate of approximately 2.5%. 7 As in other tumor models, there is considerable experimental and epidemiologic evidence indicating that HCC development is a multistage process to which multiple risk factors contribute, such as age, sex, alcohol consumption, tobacco smoke and viral heterogeneity however, these variables do not fully account for the observed clinical var...

Lack of Association between the Functional Polymorphisms in the Estrogen-Metabolizing Genes and Risk for Hepatocellular Carcinoma

“…In contrast, in agreement with our present results, some reports also showed no association between certain EME polymorphism and risk for hepatocellular carcinoma. For instance, no association of the two CYP1A1 polymorphisms, MspI and Ile462Val, was observed with the hepatocellular carcinoma risk in either chronic hepatitis B carriers or hepatitis C virus -infected patients (29,30). It was also reported that the CYP17 MspAI and COMT Val158Met are not associated with the risk for hepatitis C virus -related hepatocellular carcinoma (31).…”

UDP-Glucuronosyltransferase 1A7 Genetic Polymorphisms Are Associated with Hepatocellular Carcinoma in Japanese Patients with Hepatitis C Virus Infection

“…Recent reports of genetic polymorphisms associated with HCC in patients with chronic HCV infection include the Ϫ31Ϫ511/T-C haplotype in the promoter region of the gene for the proinflammatory cytokine IL-1␤ in the Japanese population (11), polymorphisms in the microsomal epoxide hydrolase gene in Italians (14), and polymorphisms in the enzyme cytochrome P in Caucasians (12). Although we failed to find a SNP map that predicted high susceptibility to HCC in this study, accumulating information on HCC-related SNPs may facilitate the identification of patients with high susceptibility to HCC in the future.…”

Large-scale search of single nucleotide polymorphisms for hepatocellular carcinoma susceptibility genes in patients with hepatitis C

“…[9][10][11][12][13][14][15] Recently, we reported that genetic polymorphisms in interleukin-1␤ 11 and uridine 5Ј-diphosphate-glucuronosyltransferase 1A7 12 are associated with the development of HCC in Japanese patients with chronic HCV infection. Genetic polymorphisms in CYP enzymes, 13 the microsomal epoxide hydrolase gene, 14 and the aldehyde dehydrogenase 2 gene 15 also have been reported to be associated with HCC and the severity of HCV-related liver disease. The number of candidate genes that have been examined is, however, rather limited.…”