title: Innate immune genes synergize to predict increased risk of chronic disease in hepatitis C virus infection.
abstract: Hepatitis C is a common infection with significant morbidity and mortality, and only a minority of patients successfully clear the infection. Identification of factors that influence disease progression in HCV infection is difficult owing to the lack of well-defined patient cohorts. However, recent evidence supports a role for the innate immune system in virus clearance. In this study, we investigated innate immune genes for their contribution to disease progression in a unique cohort of well-controlled HCV-infected patients. The Irish cohort of HCV patients is uniquely homogenous; patients were infected with a single genotype of HCV from contaminated anti-D Ig. We genotyped 543 infected patients, including 247 patients who spontaneously resolved infection, for natural killer (NK) cell-associated killer cell Ig-like receptors (KIR) genes and the recently reported IL28B (IFNλ3) SNP. The NK cell gene KIR2DS3 was significantly increased in patients with chronic infection [odds ratio (OR) 1.90, 95% confidence interval (CI) 1.25-2.90, P < 0.002]. The IL28B "T" allele was also significantly increased in chronically infected patients (OR 7.38, 95% CI 4.93-11.07, P < 10(-8)). The presence of both markers synergized to significantly increase the risk of chronic infection over either factor alone (OR 20.11, 95% CI 9.05-44.68, P < 10(-7)). In functional experiments, we found that IL28A significantly inhibited IFN-γ production by NK cells. Thus, we demonstrate a functional link between NK cells and type 3 IFN. Our findings may contribute to the development of a prognostic test for HCV and identify therapeutic strategies for the clinical management of HCV-infected patients.
authors.affiliation: Natural Killer Cell Group, School of Biochemistry and Immunology, Trinity College, Dublin 2, Ireland.
authors.forename: Megan M
authors.initials: MM
authors.lastname: Dring
authors.forename: Maria H
authors.initials: MH
authors.lastname: Morrison
authors.forename: Brian P
authors.initials: BP
authors.lastname: McSharry
authors.forename: Kieran J
authors.initials: KJ
authors.lastname: Guinan
authors.forename: Richard
authors.initials: R
authors.lastname: Hagan
authors.forename: Cliona
authors.initials: C
authors.lastname: O'Farrelly
authors.forename: Clair M
authors.initials: CM
authors.lastname: Gardiner
mesh_terms: D005838:Genotype; D016174:Hepacivirus / Q000276:immunology*; D006526:Hepatitis C / Q000235:genetics / Q000276:immunology*; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics*; D007378:Interleukins / Q000378:metabolism*; D007494:Ireland; D007694:Killer Cells, Natural / Q000276:immunology*; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D054340:Receptors, KIR / Q000235:genetics / Q000378:metabolism*; D012307:Risk Factors; D000095022:Interferon Lambda
chemical_list: D007378:Interleukins; D054340:Receptors, KIR; C000624353:interferon-lambda, human; D000095022:Interferon Lambda; C541358:KIR2DS3 protein, human