title: Polymorphisms of microsomal epoxide hydrolase gene and severity of HCV-related liver disease.
abstract: Factors influencing the progression of liver disease and the development of hepatocellular carcinoma (HCC) in chronic hepatitis C virus (HCV) infection are poorly understood. Inherited variations of drug-metabolizing enzyme (DME) activities may affect liver damage and cancer risk by modifying individual susceptibility to endogenous or exogenous toxic compounds. We investigated the association of liver disease severity with common alleles of microsomal epoxide hydrolase (mEH), an enzyme involved in the metabolism of highly reactive epoxide intermediates. Three polymorphisms (Tyr113His, His139Arg, and -613C/T) were analyzed by polymerase chain reaction (PCR) restriction fragment length polymorphisms (RFLPs) in 394 patients at different stages of disease, including 92 asymptomatic carriers, 109 patients with chronic hepatitis, 100 patients with cirrhosis, and 93 patients with HCC. Reference allele frequencies were obtained from 99 healthy blood donors. Allele distributions between categories were compared using the chi(2) test; odds ratios (ORs) and 95% CI were calculated to express relative risks. Allele frequencies among 99 healthy controls were as follows: 15.1% for 113His/His, 4.0% for 139Arg/Arg, and 46.5% for -613C/T. mEH 113His/His homozygotes were overrepresented in advanced stages of disease, in particular among HCC patients (27.9%; P =.03; OR, 2.2; 95% CI, 1.0-4.6). Differences were more pronounced among men and between extreme patient categories. When mEH genotypes were combined to express a metabolic phenotype, very slow metabolizers were highly prevalent among cirrhotic and HCC patients (18% vs. 3.3% in carriers; P <.001). In conclusion, mEH gene polymorphisms were significantly associated with HCV-related liver disease severity and HCC risk. Men were at higher risk than women; this might be explained by hormonal regulation of gene expression or by differential exposure to environmental toxins.
authors.affiliation: Associazione Studi Avanzati Epatiti Virali (ASAEV), Bonate Sotto (BG), Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Sonzogni
authors.forename: Laura
authors.initials: L
authors.lastname: Silvestri
authors.forename: Annalisa
authors.initials: A
authors.lastname: De Silvestri
authors.forename: Chiara
authors.initials: C
authors.lastname: Gritti
authors.forename: Luciana
authors.initials: L
authors.lastname: Foti
authors.forename: Claudio
authors.initials: C
authors.lastname: Zavaglia
authors.forename: Riccardo
authors.initials: R
authors.lastname: Bottelli
authors.forename: Mario U
authors.initials: MU
authors.lastname: Mondelli
authors.forename: Emilio
authors.initials: E
authors.lastname: Civardi
authors.forename: Enrico M
authors.initials: EM
authors.lastname: Silini
mesh_terms: D000328:Adult; D000368:Aged; D000483:Alleles; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000821:virology; D004851:Epoxide Hydrolases / Q000235:genetics*; D005091:Exons; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D005838:Genotype; D019698:Hepatitis C, Chronic / Q000235:genetics*; D006801:Humans; D008103:Liver Cirrhosis / Q000235:genetics / Q000821:virology; D008113:Liver Neoplasms / Q000235:genetics / Q000821:virology; D008297:Male; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D012150:Polymorphism, Restriction Fragment Length; D012727:Sex Characteristics
chemical_list: D004851:Epoxide Hydrolases