title: PNPLA3 rs738409 causes steatosis according to viral & IL28B genotypes in hepatitis C.
abstract: BACKGROUND
  Hepatitis C virus (HCV) is associated with a higher prevalence of steatosis compared to the general population.
  
  
  OBJECTIVE
  Our aim was to assess the impact of PNPLA3 rs738409 G-allele on steatosis in HCV patients.
  
  
  METHODS
  We included 474 HCV patients treated with peginterferon plus ribavirin. PNPLA3 rs738409 was genotyped and patients were classified according to alleles and genotypes. Steatosis was detected in 46.4% (220/474). Fibrosis was assessed by Scheuer score. Gene expression was analyzed in Huh7.5 and Huh7 cells using Real Time-PCR.
  
  
  RESULTS
  PNPLA3 allele-G was associated with steatosis [54.1% (126/233) vs. 39% (94/241)] (p = 0.0001). In HCV-1, allele-G was related to steatosis [50.6% (82/162) vs. 32.3% (53/164)] (p = 0.001), but did not in HCV-3 [61.9% (26/42) vs. 62% (31/50)] (p = 0.993). PNPLA3 allele-G was associated with steatosis in patients with IL28B-CT/TT [57.7% (82/142) vs. 37.1% (56/151)] (p = 0.0001), but did not in IL28B-CC [47.8% (43/90) vs. 42% (37/88)] (p = 0.442). Independent variables associated with steatosis were: PNPLA3 G-allele [O.R. 1.84 (CI95%: 1.06-3.21); p = 0.007], age [O.R. 1.04 (CI95%: 1.01-1.07); p = 0.017], HCV-genotype 3 [O.R. 2.46 (CI95%: 1.30-4.65); p = 0.006], HOMA > 4 [O.R. 2.72 (CI95%: 1.27-5.82); p = 0.010]. Since PNPLA3 RNA could not be detected on PBMC from HCV patients, an in vitro analysis was performed. Huh7.5 cells infected with JFH1 had a decreased PNPLA3 gene expression (fold inhibition = 3.2 ± 0.2), while Huh7 cells presented increased PNPLA3 gene expression (fold induction = 1.5 ± 0.2).
  
  
  CONCLUSIONS
  PNPLA3 allele-G modulated the development of steatosis, particularly in patients with HCV-1 and IL28B-CT/TT genotype, but was not associated with SVR. Metabolic but not viral steatosis seems to be PNPLA3 regulated. Gene interaction may result in differential PNPLA3 gene expression levels in HCV infection.
authors.affiliation: Unit for Clinical Management of Digestive Diseases and ciberehd, Valme University Hospital, Sevilla, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Ampuero
authors.affiliation: Unit for Clinical Management of Digestive Diseases and ciberehd, Valme University Hospital, Sevilla, Spain.
authors.forename: José A
authors.initials: JA
authors.lastname: Del Campo
authors.affiliation: Unit for Clinical Management of Digestive Diseases and ciberehd, Valme University Hospital, Sevilla, Spain.
authors.forename: Lourdes
authors.initials: L
authors.lastname: Rojas
authors.affiliation: Immunology Unit, Virgen del Rocio Hospital, Sevilla, Spain. ‡ Mar Hospital, Barcelona, Spain.
authors.forename: José R
authors.initials: JR
authors.lastname: García-Lozano
authors.affiliation: Mar Hospital, Barcelona, Spain.
authors.forename: Ricard
authors.initials: R
authors.lastname: Solá
authors.affiliation: Digestive Unit and ciberehd. Virgen de la Victoria University Hospital, Málaga, Spain.
authors.forename: Raúl
authors.initials: R
authors.lastname: Andrade
authors.affiliation: Virgen de la Arraixaca University Hospital, Murcia, Spain.
authors.forename: José A
authors.initials: JA
authors.lastname: Pons
authors.affiliation: Costa del Sol Hospital, Marbella, Spain.
authors.forename: José M
authors.initials: JM
authors.lastname: Navarro
authors.affiliation: Puerta de Hierro Hospital, Madrid, Spain.
authors.forename: José L
authors.initials: JL
authors.lastname: Calleja
authors.affiliation: Hepatology Unit and ciberehd. Vall d'Hebrón Hospital, Barcelona, Spain.
authors.forename: María
authors.initials: M
authors.lastname: Buti
authors.affiliation: Immunology Unit, Virgen del Rocio Hospital, Sevilla, Spain.
authors.forename: María F
authors.initials: MF
authors.lastname: González-Escribano
authors.affiliation: Hepatology Unit and ciberehd. Vall d'Hebrón Hospital, Barcelona, Spain.
authors.forename: Xavier
authors.initials: X
authors.lastname: Forns
authors.affiliation: Digestive Department, Valencia Hospital, Spain.
authors.forename: Moisés
authors.initials: M
authors.lastname: Diago
authors.affiliation: Digestive Unit and ciberehd. Carlos III Hospital, Madrid, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: García-Samaniego
authors.affiliation: Unit for Clinical Management of Digestive Diseases and ciberehd, Valme University Hospital, Sevilla, Spain.
authors.forename: Manuel
authors.initials: M
authors.lastname: Romero-Gómez
mesh_terms: D000328:Adult; D000998:Antiviral Agents / Q000627:therapeutic use; D002478:Cells, Cultured; D015331:Cohort Studies; D003430:Cross-Sectional Studies; D004359:Drug Therapy, Combination; D005234:Fatty Liver / Q000235:genetics* / Q000821:virology; D005260:Female; D020869:Gene Expression Profiling; D005838:Genotype; D016174:Hepacivirus / Q000235:genetics*; D019698:Hepatitis C, Chronic / Q000188:drug therapy / Q000235:genetics* / Q000821:virology; D006801:Humans; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000627:therapeutic use; D007372:Interferons; D007378:Interleukins / Q000235:genetics*; D008049:Lipase / Q000235:genetics*; D008099:Liver / Q000473:pathology*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D011092:Polyethylene Glycols / Q000627:therapeutic use; D012367:RNA, Viral / Q000235:genetics*; D011994:Recombinant Proteins / Q000627:therapeutic use; D012254:Ribavirin / Q000627:therapeutic use; D012307:Risk Factors; D019562:Viral Load; D000095022:Interferon Lambda; D000217:Acyltransferases; D054512:Phospholipases A2, Calcium-Independent
chemical_list: D000998:Antiviral Agents; D000077190:Interferon alpha-2; 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; C417083:peginterferon alfa-2b; C100416:peginterferon alfa-2a