title: Additive effects of HLA alleles and innate immune genes determine viral outcome in HCV infection.
abstract: BACKGROUND
  Chronic HCV infection is a leading cause of liver-related morbidity globally. The innate and adaptive immune responses are thought to be important in determining viral outcomes. Polymorphisms associated with the IFNL3 (IL28B) gene are strongly associated with spontaneous clearance and treatment outcomes.
  
  
  OBJECTIVE
  This study investigates the importance of HLA genes in the context of genetic variation associated with the innate immune genes IFNL3 and KIR2DS3.
  
  
  METHODS
  We assess the collective influence of HLA and innate immune genes on viral outcomes in an Irish cohort of women (n=319) who had been infected from a single source as well as a more heterogeneous cohort (Swiss Cohort, n=461). In the Irish cohort, a number of HLA alleles are associated with different outcomes, and the impact of IFNL3-linked polymorphisms is profound.
  
  
  RESULTS
  Logistic regression was performed on data from the Irish cohort, and indicates that the HLA-A*03 (OR 0.36 (0.15 to 0.89), p=0.027) -B*27 (OR 0.12 (0.03 to 0.45), p=<0.001), -DRB1*01:01 (OR 0.2 (0.07 to 0.61), p=0.005), -DRB1*04:01 (OR 0.31 (0.12 to 0.85, p=0.02) and the CC IFNL3 rs12979860 genotypes (OR 0.1 (0.04 to 0.23), p<0.001) are significantly associated with viral clearance. Furthermore, DQB1*02:01 (OR 4.2 (2.04 to 8.66), p=0.008), KIR2DS3 (OR 4.36 (1.62 to 11.74), p=0.004) and the rs12979860 IFNL3 'T' allele are associated with chronic infection. This study finds no interactive effect between IFNL3 and these Class I and II alleles in relation to viral clearance. There is a clear additive effect, however. Data from the Swiss cohort also confirms independent and additive effects of HLA Class I, II and IFNL3 genes in their prediction of viral outcome.
  
  
  CONCLUSIONS
  This data supports a critical role for the adaptive immune response in the control of HCV in concert with the innate immune response.
authors.affiliation: Nuffield Department of Medicine, University of Oxford, Oxford, UK.
authors.forename: Karen
authors.initials: K
authors.lastname: Fitzmaurice
authors.affiliation: Nuffield Department of Medicine, University of Oxford, Oxford, UK Institute of Emerging Infection, The Oxford Martin School, University of Oxford, Oxford, UK.
authors.forename: Jacob
authors.initials: J
authors.lastname: Hurst
authors.affiliation: Natural Killer Cell Research Group, School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College, Dublin 2, Ireland.
authors.forename: Megan
authors.initials: M
authors.lastname: Dring
authors.affiliation: University Clinic of Infectious Diseases, University Hospital Bern and University of Bern, Bern, Switzerland.
authors.forename: Andri
authors.initials: A
authors.lastname: Rauch
authors.affiliation: Institute of Microbiology, University Hospital and University of Lausanne, Lausanne, Switzerland.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: McLaren
authors.affiliation: Division of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, University of Zurich, Zurich, Switzerland.
authors.forename: Huldrych F
authors.initials: HF
authors.lastname: Günthard
authors.affiliation: Natural Killer Cell Research Group, School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College, Dublin 2, Ireland.
authors.forename: Clair
authors.initials: C
authors.lastname: Gardiner
authors.affiliation: Nuffield Department of Medicine, University of Oxford, Oxford, UK NIHR Biomedical Research Centre, John Radcliffe Hospital, Oxford, UK.
authors.forename: Paul
authors.initials: P
authors.lastname: Klenerman
mesh_terms: D056704:Adaptive Immunity / Q000235:genetics; D000293:Adolescent; D000328:Adult; D000368:Aged; D000483:Alleles; D015331:Cohort Studies; D005260:Female; D005805:Genes, MHC Class I; D005802:Genes, MHC Class II; D005838:Genotype; D015791:HLA-A3 Antigen / Q000235:genetics; D015796:HLA-B27 Antigen / Q000235:genetics; D015236:HLA-C Antigens / Q000235:genetics; D019698:Hepatitis C, Chronic / Q000235:genetics* / Q000276:immunology / Q000821:virology; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics; D007372:Interferons; D007378:Interleukins / Q000235:genetics; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D054340:Receptors, KIR / Q000235:genetics; D019562:Viral Load / Q000235:genetics / Q000276:immunology; D055815:Young Adult; D000095022:Interferon Lambda
chemical_list: D015791:HLA-A3 Antigen; D015796:HLA-B27 Antigen; D015236:HLA-C Antigens; D007372:Interferons; D007378:Interleukins; D054340:Receptors, KIR; C487960:HLA-A*03 antigen; C000624353:interferon-lambda, human; D000095022:Interferon Lambda; C541358:KIR2DS3 protein, human
keywords: HLA; Hepatitis C; Immunogenetics; Immunology in Hepatology; T Lymphocytes