title: A systematic review and meta-analysis of HCV clearance.
abstract: While hepatitis C exemplifies the role of host genetics in infectious diseases outcomes, there is no comprehensive overview of polymorphisms influencing spontaneous and/or treatment-induced hepatitis C virus clearance. We performed a systematic review and meta-analysis of host polymorphisms associated with these phenotypes. Literature search was conducted using combinations of keywords in three databases. Studies were reviewed and relevant data systematically extracted for subsequent meta-analyses. Polymorphisms from candidate gene studies were tested in two cohorts of HCV-infected patients with available genomic data. The literature search yielded 8'294 citations, among which 262 studies were selected. In the meta-analysis of 27 HLA studies, the most significant associations with spontaneous hepatitis C virus clearance included DQB1*02, DQB1*03, DRB1*04 and DRB1*11. In the meta-analysis of 16 studies of KIR genes and their HLA-ligands, KIR2DS3 was associated with both spontaneous and treatment-induced clearance, and the HLA-C2 ligand with failure to spontaneously clear the virus. In a pooled analysis of 105 candidate genes and two genome-wide association studies, we observed associations of single nucleotide polymorphisms from nine genes (EIF2AK2, IFNAR2, ITPA, MBL2, MX1, OASL, SPP1, TGFB1, TNK2) with response to interferon-based therapy. Meta-analysis of 141 studies confirmed the association of IFNL3/4 polymorphisms with spontaneous and treatment-induced hepatitis C virus clearance, even in previously underpowered groups, such as hepatitis C virus genotypes 2/3-infected patients. This study may contribute to a better understanding of hepatitis C virus immunopathogenesis and highlights the complex role of host genetics in hepatitis C virus clearance.
authors.affiliation: Infectious Diseases Service, Department of Medicine, University Hospital and University of Lausanne, Lausanne, Switzerland.
authors.forename: Emeline
authors.initials: E
authors.lastname: Gauthiez
authors.affiliation: Faculty of Medicine, University of Lausanne, Lausanne, Switzerland.
authors.forename: Ines
authors.initials: I
authors.lastname: Habfast-Robertson
authors.affiliation: Institute for Social and Preventive Medicine and Department of Medical Genetics, University Hospital and University of Lausanne, Lausanne, Switzerland.
authors.forename: Sina
authors.initials: S
authors.lastname: Rüeger
authors.affiliation: Institute for Social and Preventive Medicine and Department of Medical Genetics, University Hospital and University of Lausanne, Lausanne, Switzerland.
authors.forename: Zoltan
authors.initials: Z
authors.lastname: Kutalik
authors.affiliation: Division of Immunology and Allergy, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland.
authors.forename: Vincent
authors.initials: V
authors.lastname: Aubert
authors.affiliation: Department of Hepatology, Universitätsklinikum Leipzig, Leipzig, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Berg
authors.affiliation: Epatocentro Ticino, Lugano, Switzerland.
authors.forename: Andreas
authors.initials: A
authors.lastname: Cerny
authors.affiliation: Division of Infectious Diseases, University Hospital of Bern, Bern, Switzerland.
authors.forename: Meri
authors.initials: M
authors.lastname: Gorgievski
authors.affiliation: Storr Liver Centre, Westmead Millennium Institute, University of Sydney and Westmead Hospital, Sydney, NSW, Australia.
authors.forename: Jacob
authors.initials: J
authors.lastname: George
authors.affiliation: Department of Gastroenterology, University Hospital, Basel, Switzerland.
authors.forename: Markus H
authors.initials: MH
authors.lastname: Heim
authors.affiliation: Pourtalès Hospital, Neuchâtel, Switzerland.
authors.forename: Raffaele
authors.initials: R
authors.lastname: Malinverni
authors.affiliation: Division of Gastroenterology and Hepatology, University Hospital and University of Lausanne, Lausanne, Switzerland.
authors.forename: Darius
authors.initials: D
authors.lastname: Moradpour
authors.affiliation: Division of Gastroenterology and Hepatology, University Hospital of Zurich, Zurich, Switzerland.
authors.forename: Beat
authors.initials: B
authors.lastname: Müllhaupt
authors.affiliation: Division of Clinical Pathology and Division of Gastroenterology and Hepatology, University Hospitals, Geneva, Switzerland.
authors.forename: Francesco
authors.initials: F
authors.lastname: Negro
authors.affiliation: Division of Gastroenterology, Canton Hospital, St. Gall, Switzerland.
authors.forename: David
authors.initials: D
authors.lastname: Semela
authors.affiliation: Hepatology, Department of clinical Research, University of Bern, Bern, Switzerland.
authors.forename: Nasser
authors.initials: N
authors.lastname: Semmo
authors.affiliation: Transplantation Immunology Unit, Division of Immunology and Allergy, Department Medicine and Laboratory Medicine, Geneva University Hospital and Medical School, Geneva, Switzerland.
authors.forename: Jean
authors.initials: J
authors.lastname: Villard
authors.affiliation: Infectious Diseases Service, Department of Medicine, University Hospital and University of Lausanne, Lausanne, Switzerland.
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Bibert
authors.affiliation: Infectious Diseases Service, Department of Medicine, University Hospital and University of Lausanne, Lausanne, Switzerland.
authors.forename: Pierre-Yves
authors.identifier: 0000-0002-2208-4757
authors.initials: PY
authors.lastname: Bochud
mesh_terms: D000998:Antiviral Agents / Q000627:therapeutic use; D005838:Genotype; D006680:HLA Antigens / Q000235:genetics*; D016174:Hepacivirus / Q000187:drug effects / Q000235:genetics / Q000472:pathogenicity*; D006526:Hepatitis C / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics* / Q000821:virology*; D054884:Host-Pathogen Interactions; D006801:Humans; D016017:Odds Ratio; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D054340:Receptors, KIR / Q000235:genetics*; D000072230:Sustained Virologic Response; D016896:Treatment Outcome
chemical_list: D000998:Antiviral Agents; D006680:HLA Antigens; D054340:Receptors, KIR
keywords: hepatitis C; host genetics; spontaneous clearance; sustained virological response