title: Impact of patatin-like phospholipase-3 (rs738409 C>G) polymorphism on fibrosis progression and steatosis in chronic hepatitis C.
abstract: Only 20% of patients with chronic hepatitis C (CHC) will develop cirrhosis, and fibrosis progression remains highly unpredictable. A recent genome-wide association study identified a genetic variant in the patatin-like phospholipase-3 (PNPLA3) gene (rs738409 C>G) associated with steatosis that was further demonstrated to influence severity of fibrosis in nonalcoholic fatty liver disease. The aim of this study was to assess the impact of this polymorphism on histological liver damage and response to antiviral therapy in CHC. We recruited 537 Caucasian CHC patients from three European centers (Brussels, Belgium [n = 229]; Hannover, Germany [n = 171]; Lyon, France [n = 137]); these patients were centrally genotyped for the PNPLA3 (rs738409 C>G) polymorphism. We studied the influence of rs738409 and other variants in the PNPLA3 region on steatosis and fibrosis assessed both in a cross-sectional and longitudinal manner. Seven other variants previously associated with fibrosis progression were included. Finally, we explored the impact of rs738409 on response to standard antiviral therapy using the interferon lambda 3 (IL28B) [rs12979860 C>T] variant both as a comparator and as a positive control. After adjustment for age, sex, body mass index, alcohol consumption, and diabetes, rs738409 mutant G allele homozygote carriers remained at higher risk for steatosis (odds ratio [OR] 2.55, 95% confidence interval [CI] 1.08-6.03, P = 0.034), fibrosis (OR 3.13, 95% CI 1.50-6.51, P = 0.002), and fibrosis progression (OR 2.64, 95% CI 1.22-5.67, P = 0.013). Conversely, rs738409 was not independently associated with treatment failure (OR 1.07, 95% CI 0.46-2.49, P = 0.875) and did not influence clinical or biological variables.
  
  
  CONCLUSIONS
  The PNPLA3 (rs738409 C>G) polymorphism favors steatosis and fibrosis progression in CHC. This polymorphism may represent a valuable genetic predictor and a potential therapeutic target in CHC liver damage.
authors.affiliation: Department of Gastroenterology, Hepatopancreatology, and Digestive Oncology, Erasme Hospital, Brussels, Belgium.
authors.forename: Eric
authors.initials: E
authors.lastname: Trépo
authors.forename: Pierre
authors.initials: P
authors.lastname: Pradat
authors.forename: Andrej
authors.initials: A
authors.lastname: Potthoff
authors.forename: Yukihide
authors.initials: Y
authors.lastname: Momozawa
authors.forename: Eric
authors.initials: E
authors.lastname: Quertinmont
authors.forename: Thierry
authors.initials: T
authors.lastname: Gustot
authors.forename: Arnaud
authors.initials: A
authors.lastname: Lemmers
authors.forename: Pascale
authors.initials: P
authors.lastname: Berthillon
authors.forename: Leila
authors.initials: L
authors.lastname: Amininejad
authors.forename: Michéle
authors.initials: M
authors.lastname: Chevallier
authors.forename: Jerome
authors.initials: J
authors.lastname: Schlué
authors.forename: Hans
authors.initials: H
authors.lastname: Kreipe
authors.forename: Jacques
authors.initials: J
authors.lastname: Devière
authors.forename: Michael
authors.initials: M
authors.lastname: Manns
authors.forename: Christian
authors.initials: C
authors.lastname: Trépo
authors.forename: John
authors.initials: J
authors.lastname: Sninsky
authors.forename: Heiner
authors.initials: H
authors.lastname: Wedemeyer
authors.forename: Denis
authors.initials: D
authors.lastname: Franchimont
authors.forename: Christophe
authors.initials: C
authors.lastname: Moreno
mesh_terms: D000328:Adult; D000368:Aged; D000998:Antiviral Agents / Q000627:therapeutic use; D001530:Belgium; D003430:Cross-Sectional Studies; D018450:Disease Progression; D005234:Fatty Liver / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D005260:Female; D005602:France; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005858:Germany; D019698:Hepatitis C, Chronic / Q000188:drug therapy / Q000235:genetics* / Q000503:physiopathology; D006801:Humans; D007372:Interferons; D007378:Interleukins / Q000627:therapeutic use*; D008049:Lipase / Q000235:genetics*; D008103:Liver Cirrhosis / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D008137:Longitudinal Studies; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D016896:Treatment Outcome; D044465:White People / Q000235:genetics; D000095022:Interferon Lambda; D000217:Acyltransferases; D054512:Phospholipases A2, Calcium-Independent
chemical_list: D000998:Antiviral Agents; D007372:Interferons; D007378:Interleukins; D008049:Lipase; D008565:Membrane Proteins; C000624353:interferon-lambda, human; D000095022:Interferon Lambda; C533682:PNPLA3 protein, human; D000217:Acyltransferases; D054512:Phospholipases A2, Calcium-Independent