title: Implications of  PNPLA3 polymorphism in chronic hepatitis C patients receiving peginterferon plus ribavirin.
abstract: BACKGROUND
  Homozygosity for the PNPLA3 p.I148M polymorphism influences steatosis and fibrogenesis in chronic hepatitis C (CHC).
  
  
  OBJECTIVE
  To evaluate the effect of p.148M/M on sustained virological response (SVR) and viral kinetics in patients who underwent antiviral therapy with peg-interferon and ribavirin, stratified according to viral genotype and fibrosis severity, and secondarily, the interaction with interleukin-28B ( IL28B ) genotype on liver damage.
  
  
  METHODS
  In this observational study, we considered 602 treatment-naïve consecutive patients from tertiary referral centres in Milan and Vienna [61% genotype 1 (G1), 30% advanced fibrosis, 33% IL28B rs12979860 CC].
  
  
  RESULTS
  The p.148M/M genotype, detected in 8% of patients, did not influence SVR in the overall series (P = 0.29), but it was associated with SVR (3/17, 17% vs. 56/121, 46%; P = 0.034) and complete early viral response (4/17, 23% vs. 68/121, 56%; P = 0.018) in G1/4 patients with advanced fibrosis. After adjustment for age, viral load, IL28B CC genotype, treatment dose, and steatosis, p.148M/M remained a predictor of SVR in G1/4 patients with advanced fibrosis (OR 0.23, 95% CI 0.04-0.87). The p.148M/M genotype was associated with more advanced fibrosis in the overall series (P = 0.049), whereas the rs12979860 IL28B CC genotype only in patients negative for p.148M/M (P = 0.017), independently of age, BMI and alanine transaminase levels (OR 1.51, 95% CI 1.01-2.27).
  
  
  CONCLUSIONS
  PNPLA3 p.148M/M genotype was negatively associated with SVR and early viral kinetics independently of steatosis, albeit only in difficult-to-cure G1/4 patients with advanced fibrosis, whereas stratification for the p.148M/M PNPLA3 genotype unmasked an association between IL28B CC genotype and more severe liver fibrosis.
authors.affiliation: Department of Internal Medicine, Università degli Studi, Fondazione Ca' Granda IRCCS Ospedale Maggiore Policlinico, Milan, Italy. luca.valenti@unimi.it
authors.forename: L
authors.initials: L
authors.lastname: Valenti
authors.forename: A
authors.initials: A
authors.lastname: Aghemo
authors.forename: A F
authors.initials: AF
authors.lastname: Stättermayer
authors.forename: P
authors.initials: P
authors.lastname: Maggioni
authors.forename: S
authors.initials: S
authors.lastname: De Nicola
authors.forename: B M
authors.initials: BM
authors.lastname: Motta
authors.forename: M G
authors.initials: MG
authors.lastname: Rumi
authors.forename: P
authors.initials: P
authors.lastname: Dongiovanni
authors.forename: P
authors.initials: P
authors.lastname: Ferenci
authors.forename: M
authors.initials: M
authors.lastname: Colombo
authors.forename: S
authors.initials: S
authors.lastname: Fargion
mesh_terms: D000328:Adult; D000368:Aged; D000998:Antiviral Agents / Q000627:therapeutic use*; D004359:Drug Therapy, Combination; D005260:Female; D005838:Genotype; D019698:Hepatitis C, Chronic / Q000188:drug therapy* / Q000235:genetics* / Q000821:virology; D006801:Humans; D016898:Interferon-alpha / Q000627:therapeutic use*; D007372:Interferons; D007378:Interleukins / Q000235:genetics; D008049:Lipase / Q000235:genetics*; D008103:Liver Cirrhosis / Q000209:etiology* / Q000235:genetics; D016015:Logistic Models; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D011092:Polyethylene Glycols / Q000627:therapeutic use*; D011110:Polymorphism, Genetic; D012367:RNA, Viral; D011994:Recombinant Proteins / Q000627:therapeutic use; D012254:Ribavirin / Q000627:therapeutic use*; D016896:Treatment Outcome; D019562:Viral Load; D000095022:Interferon Lambda; D000217:Acyltransferases; D054512:Phospholipases A2, Calcium-Independent
chemical_list: D000998:Antiviral Agents; D016898:Interferon-alpha; D007372:Interferons; D007378:Interleukins; D008049:Lipase; D008565:Membrane Proteins; D011092:Polyethylene Glycols; D012367:RNA, Viral; D011994:Recombinant Proteins; D012254:Ribavirin; C000624353:interferon-lambda, human; D000095022:Interferon Lambda; C533682:PNPLA3 protein, human; D000217:Acyltransferases; D054512:Phospholipases A2, Calcium-Independent; C100416:peginterferon alfa-2a