title: Impact of cytokine gene variants on the prediction and prognosis of hepatocellular carcinoma in patients with cirrhosis.
abstract: OBJECTIVE
  Genetic polymorphisms modulate the expression of proinflammatory cytokines. We prospectively assessed the influence of 6 single nucleotide polymorphisms (SNPs) in TNFα, IL6, and IL1β genes on the risk of hepatocellular carcinoma (HCC) in patients with cirrhosis.
  
  
  METHODS
  TNFα (G-238A, C-863A, G-308A), IL6 (C-174G), and IL1β (C-31T, C-511T) SNPs were assessed in 232 alcoholics and 253 HCV-infected patients with biopsy-proven cirrhosis, prospectively followed-up and screened for HCC. Their influence on HCC development was assessed using the Kaplan-Meier method.
  
  
  RESULTS
  These variants did not influence the risk of HCC in alcoholic patients. Conversely, two variants influenced the risk of HCC occurrence in patients with HCV-related cirrhosis, namely the TNFα-308 (A) allele (HR = 2.4 [1.6-3.7], Log-rank <0.0001) and the IL1β-31 (T) allele (HR = 1.5 [1.1-2.1], Log-rank = 0.004). When stratifying HCV-infected patients into four genotypic associations expected to progressively increase TNFα and IL1β production, we observed increasing risk of HCC occurrence (Log-rank <0.0001) from group 1 to 4. The TNFα-308 (A) allele was the only genetic trait independently associated with risk of HCC in these patients, along with older age, male gender, BMI, and platelet count. These variables led to construction of a predictive score able to separate patients with HCV-related cirrhosis into three subgroups with progressively increasing 5-year cumulative incidences of 4.7%, 14.1%, and 36.3%, respectively (Log-rank <0.0001).
  
  
  CONCLUSIONS
  Genetic heterogeneity in the TNFα and IL1β gene promoters influences the risk of HCC in patients with HCV-induced cirrhosis. These genetic data, when incorporated into clinical scores, are able to refine selection of risk classes of HCC.
authors.affiliation: INSERM, U773, Centre de Recherche Biomédicale, Bichat Beaujon CRB3, University Paris 7, Paris, France.
authors.forename: Arige
authors.initials: A
authors.lastname: Tarhuni
authors.affiliation: University Paris 13-UFR SMBH/INSERM U1148, Bobigny, France; Biochemistry Unit, Jean Verdier Hospital, APHP, University Paris 13, Bondy, France.
authors.forename: Erwan
authors.initials: E
authors.lastname: Guyot
authors.affiliation: Biostatistics Unit, Pitié-Salpêtrière Hospital, AP-HP, Paris, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Rufat
authors.affiliation: University Paris 13-UFR SMBH/INSERM U1148, Bobigny, France; Biochemistry Unit, Jean Verdier Hospital, APHP, University Paris 13, Bondy, France.
authors.forename: Angela
authors.initials: A
authors.lastname: Sutton
authors.affiliation: University Paris 13-UFR SMBH/INSERM U1148, Bobigny, France; Liver Unit, Jean Verdier Hospital, APHP, University Paris 13, Bondy, France.
authors.forename: Valérie
authors.initials: V
authors.lastname: Bourcier
authors.affiliation: University Paris 13-UFR SMBH/INSERM U1148, Bobigny, France; Liver Unit, Jean Verdier Hospital, APHP, University Paris 13, Bondy, France.
authors.forename: Véronique
authors.initials: V
authors.lastname: Grando
authors.affiliation: University Paris 13-UFR SMBH/INSERM U1148, Bobigny, France; Liver Unit, Jean Verdier Hospital, APHP, University Paris 13, Bondy, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Ganne-Carrié
authors.affiliation: Liver Biobank "CRB des hôpitaux universitaires PSSD", Jean Verdier Hospital, APHP, University Paris 13, Bondy, France; Pathology Unit, Jean Verdier Hospital, APHP, University Paris 13, Bondy, France.
authors.forename: Marianne
authors.initials: M
authors.lastname: Ziol
authors.affiliation: INSERM, U773, Centre de Recherche Biomédicale, Bichat Beaujon CRB3, University Paris 7, Paris, France; University Paris 13-UFR SMBH/INSERM U1148, Bobigny, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Charnaux
authors.affiliation: University Paris 13-UFR SMBH/INSERM U1148, Bobigny, France; Liver Unit, Jean Verdier Hospital, APHP, University Paris 13, Bondy, France.
authors.forename: Michel
authors.initials: M
authors.lastname: Beaugrand
authors.affiliation: INSERM, U773, Centre de Recherche Biomédicale, Bichat Beaujon CRB3, University Paris 7, Paris, France.
authors.forename: Richard
authors.initials: R
authors.lastname: Moreau
authors.affiliation: University Paris 13-UFR SMBH/INSERM U1148, Bobigny, France; Liver Unit, Jean Verdier Hospital, APHP, University Paris 13, Bondy, France; Liver Biobank "CRB des hôpitaux universitaires PSSD", Jean Verdier Hospital, APHP, University Paris 13, Bondy, France.
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Trinchet
authors.affiliation: INSERM, U773, Centre de Recherche Biomédicale, Bichat Beaujon CRB3, University Paris 7, Paris, France.
authors.forename: Abdellah
authors.initials: A
authors.lastname: Mansouri
authors.affiliation: INSERM, U773, Centre de Recherche Biomédicale, Bichat Beaujon CRB3, University Paris 7, Paris, France; University Paris 13-UFR SMBH/INSERM U1148, Bobigny, France; Liver Unit, Jean Verdier Hospital, APHP, University Paris 13, Bondy, France. Electronic address: pierre.nahon@jvr.aphp.fr.
authors.forename: Pierre
authors.initials: P
authors.lastname: Nahon
mesh_terms: D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000276:immunology / Q000401:mortality; D016207:Cytokines / Q000235:genetics*; D005260:Female; D006801:Humans; D053583:Interleukin-1beta / Q000235:genetics; D008103:Liver Cirrhosis / Q000235:genetics*; D008113:Liver Neoplasms / Q000235:genetics* / Q000276:immunology / Q000401:mortality; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics
chemical_list: D016207:Cytokines; D053583:Interleukin-1beta; D014409:Tumor Necrosis Factor-alpha
keywords: Cytokines; Inflammation; Liver cancer; Polymorphisms