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Genetic Polymorphisms in Antioxidant Enzymes Modulate Hepatic Iron Accumulation and Hepatocellular Carcinoma Development in Patients with Alcohol-Induced Cirrhosis

¹ UPRES 3410, ² UPRES 3406, and ³ UPRES 3409, UFR Santé, Médecine et Biologie Humaine, Université Paris XIII, Bobigny, France; ⁴ Service de Biochimie and ⁵ Service d'Anatomopathologie, Hôpital Jean Verdier; ⁶ Service d'Hépato-Gastroentérologie, Hôpital Jean Verdier, Bondy, France; ⁷ Institut National de la Sante et de la Recherche Medicale U481, Faculté de Médecine Xavier Bichat; ⁸ Département MSI, Groupe Hospitalier Pitié-Salpêtrière, Paris, France; and ⁹ Service de Biochimie, Hôpital Beaujon, Clichy, France

Requests for reprints: Angela Sutton, UPRES EA 3410, UFR SMBH, Université Paris XIII, 74 Rue Marcel Cachin, 93017 Bobigny Cedex, France. Phone: 33-1-48-38-76-97; Fax: 33-1-48-02-65-03; E-mail: angela.sutton{at}jvr.ap-hop-paris.fr.

Manganese superoxide dismutase (MnSOD) converts the superoxide anion into H₂O₂, which, unless it is detoxified by glutathione peroxidase 1 (GPx1), can increase hepatic iron and can react with iron to form genotoxic compounds. We investigated the role of Ala/Val-MnSOD and Pro/Leu-GPx1 polymorphisms on hepatic iron accumulation and hepatocellular carcinoma development in patients with alcoholic cirrhosis. Genotypes were determined in 162 alcoholic patients with cirrhosis but without hepatocellular carcinoma initially, who were prospectively followed up for hepatocellular carcinoma development. We found that patients with two Val-MnSOD alleles (slow H₂O₂ production) and two Pro-GPx1 alleles (presumably quick H₂O₂ detoxification) had a lower risk of hepatocellular carcinoma development than other patients (² trend test, P = 0.001; log-rank, P = 0.0009). Indeed, hepatocellular carcinoma percentage was 0% in subjects with this "2Val-MnSOD/2Pro-GPx1" genotype versus 16%, 27%, and 32% in "2Val-MnSOD/1or2Leu-GPx1," "1or2Ala-MnSOD/2Pro-GPx1," and "1or2Ala-MnSOD/1or2Leu-GPx1" patients, respectively. The percentage of patients with stainable hepatic iron increased progressively with these genotypic associations: 22%, 28%, 50%, and 53%, respectively (² trend test, P = 0.005). Stainable iron was a risk factor for hepatocellular carcinoma (log-rank, P = 0.0002; relative risk, 3.40). In conclusion, polymorphisms in antioxidant enzymes modulate hepatic iron accumulation and hepatocellular carcinoma development in French alcoholic patients with cirrhosis. (Cancer Res 2006; 66(5): 2844-52)

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