title: KIR, HLA, and IL28B variant predict response to antiviral therapy in genotype 1 chronic hepatitis C patients in Japan.
abstract: Natural killer cell responses play a crucial role in virus clearance by the innate immune system. Although the killer immunoglobulin-like receptor (KIR) in combination with its cognate human leukocyte antigen (HLA) ligand, especially KIR2DL3-HLA-C1, is associated with both treatment-induced and spontaneous clearance of hepatitis C virus (HCV) infection in Caucasians, these innate immunity genes have not been fully clarified in Japanese patients. We therefore investigated 16 KIR genotypes along with HLA-B and -C ligands and a genetic variant of interleukin (IL) 28B (rs8099917) in 115 chronic hepatitis C genotype 1 patients who underwent pegylated-interferon-α2b (PEG-IFN) and ribavirin therapy. HLA-Bw4 was significantly associated with a sustained virological response (SVR) to treatment (P = 0.017; odds ratio [OR] = 2.50, ), as was the centromeric A/A haplotype of KIR (P = 0.015; OR 3.37). In contrast, SVR rates were significantly decreased in patients with KIR2DL2 or KIR2DS2 (P = 0.015; OR = 0.30, and P = 0.025; OR = 0.32, respectively). Multivariate logistic regression analysis subsequently identified the IL28B TT genotype (P = 0.00009; OR = 6.87, 95% confidence interval [CI] = 2.62 - 18.01), KIR2DL2/HLA-C1 (P = 0.014; OR = 0.24, 95% CI = 0.08 - 0.75), KIR3DL1/HLA-Bw4 (P = 0.008, OR = 3.32, 95% CI = 1.37 - 8.05), and white blood cell count at baseline (P = 0.009; OR = 3.32, 95% CI = 1.35 - 8.16) as independent predictive factors of an SVR. We observed a significant association between the combination of IL28B TT genotype and KIR3DL1-HLA-Bw4 in responders (P = 0.0019), whereas IL28B TT along with KIR2DL2-HLA-C1 was related to a non-response (P = 0.0067). In conclusion, combinations of KIR3DL1/HLA-Bw4, KIR2DL2/HLA-C1, and a genetic variant of the IL28B gene are predictive of the response to PEG-IFN and ribavirin therapy in Japanese patients infected with genotype 1b HCV.
authors.affiliation: Division of Hepatology and Gastroenterology, Department of Medicine, Shinshu University School of Medicine, Matsumoto, Japan.
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Nozawa
authors.affiliation: Division of Hepatology and Gastroenterology, Department of Medicine, Shinshu University School of Medicine, Matsumoto, Japan.
authors.forename: Takeji
authors.initials: T
authors.lastname: Umemura
authors.affiliation: Division of Hepatology and Gastroenterology, Department of Medicine, Shinshu University School of Medicine, Matsumoto, Japan.
authors.forename: Satoru
authors.initials: S
authors.lastname: Joshita
authors.affiliation: Department of Pharmacy, Shinshu University Hospital, Matsumoto, Japan.
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Katsuyama
authors.affiliation: Division of Hepatology and Gastroenterology, Department of Medicine, Shinshu University School of Medicine, Matsumoto, Japan.
authors.forename: Soichiro
authors.initials: S
authors.lastname: Shibata
authors.affiliation: Division of Hepatology and Gastroenterology, Department of Medicine, Shinshu University School of Medicine, Matsumoto, Japan.
authors.forename: Takefumi
authors.initials: T
authors.lastname: Kimura
authors.affiliation: Division of Hepatology and Gastroenterology, Department of Medicine, Shinshu University School of Medicine, Matsumoto, Japan.
authors.forename: Susumu
authors.initials: S
authors.lastname: Morita
authors.affiliation: Division of Hepatology and Gastroenterology, Department of Medicine, Shinshu University School of Medicine, Matsumoto, Japan.
authors.forename: Michiharu
authors.initials: M
authors.lastname: Komatsu
authors.affiliation: Division of Hepatology and Gastroenterology, Department of Medicine, Shinshu University School of Medicine, Matsumoto, Japan.
authors.forename: Akihiro
authors.initials: A
authors.lastname: Matsumoto
authors.affiliation: Division of Hepatology and Gastroenterology, Department of Medicine, Shinshu University School of Medicine, Matsumoto, Japan.
authors.forename: Eiji
authors.initials: E
authors.lastname: Tanaka
authors.affiliation: Department of Legal Medicine, Shinshu University School of Medicine, Matsumoto, Japan.
authors.forename: Masao
authors.initials: M
authors.lastname: Ota
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000998:Antiviral Agents / Q000008:administration & dosage*; D005260:Female; D006680:HLA Antigens / Q000235:genetics* / Q000276:immunology; D019698:Hepatitis C, Chronic / Q000188:drug therapy* / Q000235:genetics* / Q000276:immunology; D006801:Humans; D016898:Interferon-alpha / Q000008:administration & dosage*; D007372:Interferons; D007378:Interleukins / Q000235:genetics* / Q000276:immunology; D008297:Male; D008875:Middle Aged; D011092:Polyethylene Glycols / Q000008:administration & dosage*; D054340:Receptors, KIR / Q000235:genetics* / Q000276:immunology; D011994:Recombinant Proteins / Q000008:administration & dosage; D000095022:Interferon Lambda
chemical_list: D000998:Antiviral Agents; D006680:HLA Antigens; D016898:Interferon-alpha; D007372:Interferons; D007378:Interleukins; D011092:Polyethylene Glycols; D054340:Receptors, KIR; D011994:Recombinant Proteins; C000624353:interferon-lambda, human; D000095022:Interferon Lambda; C100416:peginterferon alfa-2a