title: The impact of PNPLA3 (rs738409 C>G) polymorphisms on liver histology and long-term clinical outcome in chronic hepatitis B patients.
abstract: OBJECTIVE
  We aimed to assess the association between the patatin-like phospholipase domain-containing-3 (PNPLA3) I148M polymorphism, liver histology and long-term outcome in chronic hepatitis B (CHB) patients.
  
  
  METHODS
  We enrolled 531 consecutive treatment naïve CHB patients diagnosed from 1985 to 2012 with an available liver biopsy for reassessment, and sample for genetic testing. Data on all-cause mortality and hepatocellular carcinoma (HCC) at long-term follow-up were obtained from national database registries.
  
  
  RESULTS
  The prevalence of steatohepatitis increased with PNPLA3 CC (14%), CG (20%) and GG (43%) (P < 0.001). The association was altered by both gender (P = 0.010) and overweight (P = 0.015): the effect of PNPLA3 on steatohepatitis was most pronounced among non-overweight females (adjusted OR 13.4, 95%CI: 3.7-51.6, P < 0.001), and non-overweight males (adjusted OR 2.4, 95%CI: 1.4-4.3, P = 0.002). Furthermore, PNPLA3 GG genotype was associated with iron depositions (OR 2.8, 95%CI: 1.2-6.4, P = 0.014) and lobular inflammation (OR 2.2, 95%CI: 1.1-4.5, P = 0.032), but not with advanced fibrosis (OR 1.1, 95%CI: 0.7-1.8, P = 0.566). The median follow-up was 10.1 years (interquartile range 5.6 - 15.8), during which 13 patients developed HCC and 28 died. Steatohepatitis was associated with all-cause mortality [Hazard ratio (HR) 3.1, 95%CI: 1.3-7.3, P = 0.006] and HCC (HR 2.8, 95%CI: 0.9-9.2, P = 0.078), but no significant association was observed for PNPLA3.
  
  
  CONCLUSIONS
  In this cohort of biopsied CHB patients, PNPLA3 was independently associated with steatosis, steatohepatitis, lobular inflammation and iron depositions, but not with advanced fibrosis, HCC development or all-cause mortality. The effect of PNPLA3 on steatohepatitis was particularly pronounced among female patients without severe overweight.
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center, Rotterdam, The Netherlands.
authors.forename: Willem P
authors.initials: WP
authors.lastname: Brouwer
authors.forename: Adriaan J
authors.initials: AJ
authors.lastname: van der Meer
authors.forename: Andre
authors.initials: A
authors.lastname: Boonstra
authors.forename: Suzan D
authors.initials: SD
authors.lastname: Pas
authors.forename: Robert J
authors.initials: RJ
authors.lastname: de Knegt
authors.forename: Rob A
authors.initials: RA
authors.lastname: de Man
authors.forename: Bettina E
authors.initials: BE
authors.lastname: Hansen
authors.forename: Fiebo J W
authors.initials: FJ
authors.lastname: ten Kate
authors.forename: Harry L A
authors.initials: HL
authors.lastname: Janssen
mesh_terms: D001835:Body Weight; D006528:Carcinoma, Hepatocellular / Q000453:epidemiology / Q000235:genetics; D005234:Fatty Liver / Q000453:epidemiology* / Q000235:genetics; D005260:Female; D019694:Hepatitis B, Chronic / Q000150:complications / Q000235:genetics* / Q000473:pathology; D006801:Humans; D007501:Iron / Q000378:metabolism; D008049:Lipase / Q000235:genetics*; D008099:Liver / Q000473:pathology*; D008113:Liver Neoplasms / Q000453:epidemiology / Q000235:genetics; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D015995:Prevalence; D016016:Proportional Hazards Models; D012737:Sex Factors; D000217:Acyltransferases; D054512:Phospholipases A2, Calcium-Independent
chemical_list: D007501:Iron; D008049:Lipase; D008565:Membrane Proteins; C533682:PNPLA3 protein, human; D000217:Acyltransferases; D054512:Phospholipases A2, Calcium-Independent
keywords: adiponutrin; liver histology; patatin-like phospholipase domain-containing 3; viral hepatitis