title: Genome-wide association study identifies variants associated with progression of liver fibrosis from HCV infection.
abstract: OBJECTIVE
  Polymorphisms in IL28B were shown to affect clearance of hepatitis C virus (HCV) infection in genome-wide association (GWA) studies. Only a fraction of patients with chronic HCV infection develop liver fibrosis, a process that might also be affected by genetic factors. We performed a 2-stage GWA study of liver fibrosis progression related to HCV infection.
  
  
  METHODS
  We studied well-characterized HCV-infected patients of European descent who underwent liver biopsies before treatment. We defined various liver fibrosis phenotypes on the basis of METAVIR scores, with and without taking the duration of HCV infection into account. Our GWA analyses were conducted on a filtered primary cohort of 1161 patients using 780,650 single nucleotide polymorphisms (SNPs). We genotyped 96 SNPs with P values <5 × 10(-5) from an independent replication cohort of 962 patients. We then assessed the most interesting replicated SNPs using DNA samples collected from 219 patients who participated in separate GWA studies of HCV clearance.
  
  
  RESULTS
  In the combined cohort of 2342 HCV-infected patients, the SNPs rs16851720 (in the total sample) and rs4374383 (in patients who received blood transfusions) were associated with fibrosis progression (P(combined) = 8.9 × 10(-9) and 1.1 × 10(-9), respectively). The SNP rs16851720 is located within RNF7, which encodes an antioxidant that protects against apoptosis. The SNP rs4374383, together with another replicated SNP, rs9380516 (P(combined) = 5.4 × 10(-7)), were linked to the functionally related genes MERTK and TULP1, which encode factors involved in phagocytosis of apoptotic cells by macrophages.
  
  
  CONCLUSIONS
  Our GWA study identified several susceptibility loci for HCV-induced liver fibrosis; these were linked to genes that regulate apoptosis. Apoptotic control might therefore be involved in liver fibrosis.
authors: Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Necker Medical School, INSERM Unité 980, Paris, France; University Paris Descartes, Paris, France.
authors: Etienne
authors: E
authors: Patin
authors: Department of Medical Genetics, University of Lausanne, Lausanne, Switzerland; Swiss Institute of Bioinformatics, Lausanne, Switzerland.
authors: Zoltán
authors: Z
authors: Kutalik
authors: Laboratory of Immunity and Infection, INSERM UMR-S 945, UPMC Université Paris 6, Groupe Hospitalier Pitié-Salpêtrière AP-HP, Paris, France.
authors: Julien
authors: J
authors: Guergnon
authors: Infectious Diseases Service, Department of Medicine, University Hospital and University of Lausanne, Lausanne, Switzerland.
authors: Stéphanie
authors: S
authors: Bibert
authors: University Paris Descartes, Paris, France; Département d'Hépatologie, INSERM Unité 1016, Groupe Hospitalier Cochin-Hôtel Dieu-Broca, Paris, France.
authors: Bertrand
authors: B
authors: Nalpas
authors: Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Necker Medical School, INSERM Unité 980, Paris, France; University Paris Descartes, Paris, France; St Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, New York.
authors: Emmanuelle
authors: E
authors: Jouanguy
authors: Biopredictive, Paris, France.
authors: Mona
authors: M
authors: Munteanu
authors: University Paris Descartes, Paris, France; Département d'Hépatologie, INSERM Unité 1016, Groupe Hospitalier Cochin-Hôtel Dieu-Broca, Paris, France.
authors: Laurence
authors: L
authors: Bousquet
authors: Laboratoire d'Immunologie et de Génétique des Maladies Parasitaires, INSERM-UMR 906/Université de la Méditerranée, Marseilles, France.
authors: Laurent
authors: L
authors: Argiro
authors: Laboratoire Alphabio, Hôpital Ambroise Paré, Marseilles, France.
authors: Philippe
authors: P
authors: Halfon
authors: CEA, Institut de Génomique, Centre National de Génotypage, Evry, France.
authors: Anne
authors: A
authors: Boland
authors: Division of Gastroenterology and Hepatology, University Hospital, Zurich, Switzerland.
authors: Beat
authors: B
authors: Müllhaupt
authors: Division of Gastroenterology, Canton Hospital, St Gallen, Switzerland.
authors: David
authors: D
authors: Semela
authors: Hepatology, Department of Clinical Research, University Clinic for Visceral Surgery and Medicine, Bern, Switzerland.
authors: Jean-François
authors: JF
authors: Dufour
authors: Division of Gastroenterology and Hepatology, University Hospital, Basel, Switzerland.
authors: Markus H
authors: MH
authors: Heim
authors: Centre Hospitalier Universitaire Vaudois, University of Lausanne, Lausanne, Switzerland.
authors: Darius
authors: D
authors: Moradpour
authors: Clinica Moncucco, Lugano, Switzerland.
authors: Andreas
authors: A
authors: Cerny
authors: Pourtalès Hospital, Neuchâtel, Switzerland.
authors: Raffaele
authors: R
authors: Malinverni
authors: Institute for Medical Microbiology, University Hospital, Basel, Switzerland.
authors: Hans
authors: H
authors: Hirsch
authors: Institute of Medical Microbiology, Bellinzona, Switzerland.
authors: Gladys
authors: G
authors: Martinetti
authors: Storr Liver Unit, Westmead Millennium Institute and Westmead Hospital, University of Sydney and University of Sydney Medical Foundation, Sydney, Australia; INSERM Unité 785, Liver Hepatology Centre, Paul Brousse Hospital, University Paris-XI, Villejuif, France.
authors: Vijayaprakash
authors: V
authors: Suppiah
authors: Institute for Immunology and Allergy Research, Westmead Millennium Institute, University of Sydney, Sydney, Australia.
authors: Graeme
authors: G
authors: Stewart
authors: Institute for Immunology and Allergy Research, Westmead Millennium Institute, University of Sydney, Sydney, Australia.
authors: David R
authors: DR
authors: Booth
authors: Storr Liver Unit, Westmead Millennium Institute and Westmead Hospital, University of Sydney and University of Sydney Medical Foundation, Sydney, Australia.
authors: Jacob
authors: J
authors: George
authors: Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Necker Medical School, INSERM Unité 980, Paris, France; University Paris Descartes, Paris, France; St Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, New York.
authors: Jean-Laurent
authors: JL
authors: Casanova
authors: INSERM Unité 785, Liver Hepatology Centre, Paul Brousse Hospital, University Paris-XI, Villejuif, France.
authors: Christian
authors: C
authors: Bréchot
authors: Center for the Study of Hepatitis C, Rockefeller University, New York, New York.
authors: Charles M
authors: CM
authors: Rice
authors: Division of Gastroenterology and Hepatology, Weill Cornell Medical College, New York, New York.
authors: Andrew H
authors: AH
authors: Talal
authors: Division of Gastroenterology and Hepatology, Weill Cornell Medical College, New York, New York.
authors: Ira M
authors: IM
authors: Jacobson
authors: Service d'Hépato-gastroentérologie, Hôpital Saint-Joseph, Marseilles, France.
authors: Marc
authors: M
authors: Bourlière
authors: Laboratory of Immunity and Infection, INSERM UMR-S 945, UPMC Université Paris 6, Groupe Hospitalier Pitié-Salpêtrière AP-HP, Paris, France.
authors: Ioannis
authors: I
authors: Theodorou
authors: Université Pierre et Marie Curie, Service d'Hépato-gastroentérologie, Hôpital Pitié-Salpêtrière (AP-HP), Paris, France.
authors: Thierry
authors: T
authors: Poynard
authors: Divisions of Gastroenterology and Hepatology and of Clinical Pathology, University Hospital, Geneva, Switzerland.
authors: Francesco
authors: F
authors: Negro
authors: University Paris Descartes, Paris, France; Département d'Hépatologie, INSERM Unité 1016, Groupe Hospitalier Cochin-Hôtel Dieu-Broca, Paris, France.
authors: Stanislas
authors: S
authors: Pol
authors: Infectious Diseases Service, Department of Medicine, University Hospital and University of Lausanne, Lausanne, Switzerland. Electronic address: pierre-yves.bochud@chuv.ch.
authors: Pierre-Yves
authors: PY
authors: Bochud
authors: Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Necker Medical School, INSERM Unité 980, Paris, France; University Paris Descartes, Paris, France; St Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, New York. Electronic address: laurent.abel@inserm.fr.
authors: Laurent
authors: L
authors: Abel
mesh_terms: D000328:Adult; D017209:Apoptosis / Q000235:genetics; D018450:Disease Progression; D005136:Eye Proteins / Q000235:genetics; D005260:Female; D055106:Genome-Wide Association Study; D005838:Genotype; D016174:Hepacivirus; D019698:Hepatitis C, Chronic / Q000150:complications* / Q000821:virology; D006801:Humans; D008049:Lipase / Q000235:genetics; D008103:Liver Cirrhosis / Q000235:genetics* / Q000821:virology; D016015:Logistic Models; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D016016:Proportional Hazards Models; D011518:Proto-Oncogene Proteins / Q000235:genetics; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics; D044767:Ubiquitin-Protein Ligases / Q000235:genetics; D055815:Young Adult; D000076202:c-Mer Tyrosine Kinase; D000217:Acyltransferases; D054512:Phospholipases A2, Calcium-Independent
chemical_list: D005136:Eye Proteins; D008049:Lipase; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D020794:Receptor Protein-Tyrosine Kinases; D044767:Ubiquitin-Protein Ligases; D000076202:c-Mer Tyrosine Kinase; C105443:TULP1 protein, human; C118307:RNF7 protein, human; C097072:MERTK protein, human; C533682:PNPLA3 protein, human; D000217:Acyltransferases; D054512:Phospholipases A2, Calcium-Independent