title: Myeloperoxidase and superoxide dismutase 2 polymorphisms comodulate the risk of hepatocellular carcinoma and death in alcoholic cirrhosis.
abstract: Alcohol increases reactive oxygen species (ROS) formation in hepatocyte mitochondria and by reduced nicotinamide adenine dinucleotide phosphate oxidases and myeloperoxidase (MPO) in Kupffer cells and liver-infiltrating neutrophils. Manganese superoxide dismutase (MnSOD) converts superoxide anion into hydrogen peroxide, which, unless detoxified by glutathione peroxidase or catalase (CAT), can form the hydroxyl radical with iron. Our aim was to determine whether Ala16Val-superoxide dismutase 2 (SOD2), G-463A-MPO, or T-262C-CAT dimorphisms modulate the risks of hepatocellular carcinoma (HCC) and death in alcoholic cirrhosis. Genotypes and the hepatic iron score were assessed in 190 prospectively followed patients with alcoholic cirrhosis. During follow-up (61.1 +/- 2.7 months), 51 patients developed HCC, and 71 died. The T-262C-CAT dimorphism did not modify hepatic iron, HCC, or death. The GG-MPO genotype did not modify iron but increased the risks of HCC and death. The hazard ratio (HR) was 4.7 (2.1-10.1) for HCC and 3.6 (1.9-6.7) for death. Carriage of one or two Ala-SOD2 allele(s) was associated with higher liver iron scores and higher risks of HCC and death. The 5-year incidence of HCC was 34.4% in patients with both the GG-MPO genotype and one or two Ala-SOD2 alleles, 5.1% in patients with only one of these two traits, and 0% in patients with none of these traits. Corresponding 5-year death rates were 37.6%, 11.6%, and 5%.
  
  
  CONCLUSIONS
  The combination of the GG-MPO genotype (leading to high MPO expression) and at least one Ala-SOD2 allele (associated with high liver iron score) markedly increased the risks of HCC occurrence and death in patients with alcoholic cirrhosis.
authors.affiliation: Service d'Hépatologie, Hôpital Jean Verdier, AP-HP, Bondy, France. pierre.nahon@jvr.aphp.fr
authors.forename: Pierre
authors.initials: P
authors.lastname: Nahon
authors.forename: Angela
authors.initials: A
authors.lastname: Sutton
authors.forename: Pierre
authors.initials: P
authors.lastname: Rufat
authors.forename: Marianne
authors.initials: M
authors.lastname: Ziol
authors.forename: Hassan
authors.initials: H
authors.lastname: Akouche
authors.forename: Christelle
authors.initials: C
authors.lastname: Laguillier
authors.forename: Nathalie
authors.initials: N
authors.lastname: Charnaux
authors.forename: Nathalie
authors.initials: N
authors.lastname: Ganne-Carrié
authors.forename: Véronique
authors.initials: V
authors.lastname: Grando-Lemaire
authors.forename: Gisèle
authors.initials: G
authors.lastname: N'Kontchou
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Trinchet
authors.forename: Liliane
authors.initials: L
authors.lastname: Gattegno
authors.forename: Dominique
authors.initials: D
authors.lastname: Pessayre
authors.forename: Michel
authors.initials: M
authors.lastname: Beaugrand
mesh_terms: D000368:Aged; D000483:Alleles; D006528:Carcinoma, Hepatocellular / Q000453:epidemiology / Q000235:genetics* / Q000378:metabolism; D002374:Catalase / Q000235:genetics / Q000378:metabolism; D005260:Female; D005500:Follow-Up Studies; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D006801:Humans; D015994:Incidence; D007501:Iron / Q000378:metabolism; D053208:Kaplan-Meier Estimate; D008099:Liver / Q000378:metabolism; D008104:Liver Cirrhosis, Alcoholic / Q000378:metabolism / Q000401:mortality*; D008113:Liver Neoplasms / Q000453:epidemiology / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009195:Peroxidase / Q000235:genetics* / Q000378:metabolism; D011110:Polymorphism, Genetic / Q000235:genetics*; D011446:Prospective Studies; D012189:Retrospective Studies; D012307:Risk Factors; D013482:Superoxide Dismutase / Q000235:genetics* / Q000378:metabolism; D000099156:Superoxide Dismutase 2
chemical_list: D002374:Catalase; D007501:Iron; D009195:Peroxidase; D013482:Superoxide Dismutase; D000099156:Superoxide Dismutase 2