Genetic dimorphism in superoxide dismutase and susceptibility to alcoholic cirrhosis, hepatocellular carcinoma, and death

Background & Aims: A genetic dimorphism encodes for either alanine (Ala) or valine (Val) in the mitochondrial targeting sequence of manganese superoxide dismutase (MnSOD), and modulates its mitochondrial import. However, the role of this dimorphism in the susceptibility of alcoholic patients to develop cirrhosis is controversial, and its influence on the occurrence of hepatocellular carcinoma (HCC) and death in patients with alcoholic cirrhosis is unknown. Methods: We compared MnSOD genotypes in 94 control subjects and 264 patients with alcoholic cirrhosis. Patients were included at the time of the first liver biopsy examination showing cirrhosis, and were followed-up prospectively. Results: Alcohol consumption was similar, whatever the patients' genotype. At inclusion, the percentage of Val/Val homozygotes was lower in patients than in controls (16% vs. 31%), whereas the percentage of Ala/Ala homozygotes was higher in patients than in controls (30% vs. 21%) (P =.008). During follow-up evaluation, only 9% of Val/Val patients developed HCC, vs. 30% and 29% of Ala/Val and Ala/Ala patients, respectively (P =.02). Only 28% of Val/Val patients died or were transplanted, vs. 49% and 50% of Ala/Val and Ala/Ala patients, respectively (P =.03). Because of the progressive decrease in surviving Ala patients, the genotypic distribution in patients surviving for 5 or 10 years no longer differed from the genotypic distribution in controls. Conclusions: The presence of at least I Ala MnSOD allele increases the risk for developing cirrhosis in French alcoholics, and increases the rates of HCC development and death in cirrhotic patients.