Prediction of progression to cirrhosis by a glutathione S-transferase P1 polymorphism in subjects with hereditary hemochromatosis.

Oxidative stress plays an important pathogenic role in hereditary hemochromatosis (HHC) and chronic hepatitis C virus infection (CHC). Several enzymes involved in the degradation of reactive oxidants and xenobiotics, such as glutathione S-transferase P1 (GSTP1) and manganese superoxide dismutase (MnSOD), reveal polymorphisms that affect their antioxidant capacity and may therefore modulate the progression to cirrhosis. Our objective was to establish the role of the functional polymorphisms of GSTP1 (codon 105 Ile-->Val) and MnSOD (codon 16 of precursor protein Ala-->Val) on the evolution of cirrhosis in patients with HHC and CHC. One hundred seventy-two patients with HHC who were homozygous for the C282Y mutation and 285 patients with CHC underwent liver biopsy and genotyping for the GSTP1 and MnSOD polymorphisms. In HHC, the GSTP1 Val/Val genotype was more common in patients with than in those without cirrhosis (14.8% vs 2.1%, P = .009), whereas the distribution of MnSOD variants was not different. Logistic regression analysis identified GSTP1 Val/Val genotype, serum ferritin level, male sex, and age as independent predictors for the presence of cirrhosis. The odds ratio for the GSTP1 Val/Val genotype for the development of cirrhosis was 3.85 (95% confidence interval, 1.18-12.62; P = .03). However, in patients with CHC, the GSTP1 and MnSOD genotypes were not associated with cirrhosis. Cirrhosis is more likely to develop in C282Y homozygotes with the GSTP1 Val/Val genotype than in those with non-Val/Val genotypes, which in part explains the variable phenotypic expression of HHC and highlights the central role of oxidative stress in its pathogenesis.