title: DEPDC5 variants increase fibrosis progression in Europeans with chronic hepatitis C virus infection.
abstract: Chronic hepatitis C virus (HCV) infection may progress to cirrhosis and hepatocellular carcinoma (HCC). Recently, two genetic variants, DEPDC5 rs1012068 and MICA rs2596542, were associated with the onset of HCC in Asian subjects with chronic HCV infection. The aim of the present study was to analyze whether DEPDC5 and MICA genetic variants were associated with liver disease progression in European subjects with chronic HCV infection. In a Northern Italian discovery cohort (n = 477), neither DEPDC5 rs1012068 nor MICA rs2596542 were associated with HCC (n = 150). However, DEPDC5 rs1012068 was independently associated with cirrhosis (n = 300; P = 0.049). The association of rs1012068 with moderate to severe fibrosis was confirmed in an independent cross-sectional German cohort (n = 415; P = 0.006). Furthermore, DEPDC5 rs1012068 predicted faster fibrosis progression in a prospective cohort (n = 247; P = 0.027). Next, we examined the distribution of nonsynonymous DEPDC5 variants in the overall cross-sectional cohort (n = 912). The presence of at least one variant increased the risk of moderate/severe fibrosis by 54% (P = 0.040). To understand the molecular mechanism underlying the genetic association of DEPDC5 variants with fibrosis progression, we performed in vitro studies on immortalized hepatic stellate cells (LX-2). In these cells, down-regulation of DEPDC5 resulted in increased expression of β-catenin and production of its target matrix metallopeptidase 2 (MMP2), a secreted enzyme involved in fibrosis progression.
  
  
  CONCLUSIONS
  DEPDC5 variants increase fibrosis progression in European subjects with chronic HCV infection. Our findings suggest that DEPDC5 down-regulation may contribute to HCV-related fibrosis by increasing MMP2 synthesis through the β-catenin pathway.
authors.affiliation: Department of Molecular and Clinical Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
authors.forename: Maria Antonella
authors.initials: MA
authors.lastname: Burza
authors.affiliation: Department of Molecular and Clinical Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
authors.forename: Benedetta Maria
authors.initials: BM
authors.lastname: Motta
authors.affiliation: Department of Molecular and Clinical Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
authors.forename: Rosellina Margherita
authors.initials: RM
authors.lastname: Mancina
authors.affiliation: Department of Molecular and Clinical Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
authors.forename: Piero
authors.initials: P
authors.lastname: Pingitore
authors.affiliation: Department of Molecular and Clinical Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
authors.forename: Carlo
authors.initials: C
authors.lastname: Pirazzi
authors.affiliation: Clinical Nutrition Unit, Department of Medical and Surgical Sciences, Magna Graecia University, Catanzaro, Italy.
authors.forename: Saverio Massimo
authors.initials: SM
authors.lastname: Lepore
authors.affiliation: Department of Experimental and Clinical Medicine, Magna Graecia University, Catanzaro, Italy.
authors.forename: Rocco
authors.initials: R
authors.lastname: Spagnuolo
authors.affiliation: Department of Experimental and Clinical Medicine, Magna Graecia University, Catanzaro, Italy.
authors.forename: Patrizia
authors.initials: P
authors.lastname: Doldo
authors.affiliation: Clinical Nutrition Unit, Department of Medical and Surgical Sciences, Magna Graecia University, Catanzaro, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Russo
authors.affiliation: Clinical Nutrition Unit, Department of Medical and Surgical Sciences, Magna Graecia University, Catanzaro, Italy.
authors.forename: Veronica
authors.initials: V
authors.lastname: Lazzaro
authors.affiliation: Department of Gastroenterology and Rheumatology, Section of Hepatology, University Hospital, Leipzig, Germany.
authors.forename: Janett
authors.initials: J
authors.lastname: Fischer
authors.affiliation: Department of Gastroenterology and Rheumatology, Section of Hepatology, University Hospital, Leipzig, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Berg
authors.affiliation: Department of Gastroenterology, Fondazione IRCCS Ca' Granda Ospedale Policlinico Milano, Milan, Italy.
authors.forename: Alessio
authors.initials: A
authors.lastname: Aghemo
authors.affiliation: Virology Program, INGM-Istituto Nazionale di Genetica Molecolare "Romeo ed Enrica Invernizzi", Milan, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Cheroni
authors.affiliation: Virology Program, INGM-Istituto Nazionale di Genetica Molecolare "Romeo ed Enrica Invernizzi", Milan, Italy.
authors.forename: Raffaele
authors.initials: R
authors.lastname: De Francesco
authors.affiliation: Università degli Studi di Milano, Fondazione IRCCS Ca'Granda Ospedale Policlinico Milano, Department of Pathophysiology and Transplantation, Milan, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Fargion
authors.affiliation: Department of Gastroenterology, Fondazione IRCCS Ca' Granda Ospedale Policlinico Milano, Milan, Italy.|Università degli Studi di Milano, Fondazione IRCCS Ca'Granda Ospedale Policlinico Milano, Department of Pathophysiology and Transplantation, Milan, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Colombo
authors.affiliation: Department of Internal Medicine, Hospital Oberndorf, Teaching Hospital of the Paracelsus Private University of Salzburg, Oberndorf, Austria.
authors.forename: Christian
authors.initials: C
authors.lastname: Datz
authors.affiliation: Department of Gastroenterology and Hepatology, University Hospital of Zürich, Rämistrasse 100, CH-8091, Zürich, Switzerland.
authors.forename: Felix
authors.initials: F
authors.lastname: Stickel
authors.affiliation: Università degli Studi di Milano, Fondazione IRCCS Ca'Granda Ospedale Policlinico Milano, Department of Pathophysiology and Transplantation, Milan, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Valenti
authors.affiliation: Department of Molecular and Clinical Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.|Clinical Nutrition Unit, Department of Medical and Surgical Sciences, Magna Graecia University, Catanzaro, Italy.|Department of Cardiology, Sahlgrenska University Hospital, Gothenburg, Sweden.
authors.forename: Stefano
authors.initials: S
authors.lastname: Romeo
mesh_terms: D006528:Carcinoma, Hepatocellular / Q000209:etiology*; D003430:Cross-Sectional Studies; D018450:Disease Progression; D005260:Female; D020690:GTPase-Activating Proteins; D014644:Genetic Variation; D005858:Germany; D019698:Hepatitis C, Chronic / Q000150:complications* / Q000235:genetics*; D015395:Histocompatibility Antigens Class I / Q000235:genetics; D006801:Humans; D007558:Italy; D008103:Liver Cirrhosis / Q000209:etiology*; D008113:Liver Neoplasms / Q000209:etiology*; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D012097:Repressor Proteins / Q000235:genetics*; D013557:Switzerland; D044465:White People
chemical_list: C000590398:DEPDC5 protein, human; D020690:GTPase-Activating Proteins; D015395:Histocompatibility Antigens Class I; C099187:MHC class I-related chain A; D012097:Repressor Proteins