title: Association of gene expression involving innate immunity and genetic variation in interleukin 28B with antiviral response.
abstract: Innate immunity plays an important role in host antiviral response to hepatitis C viral (HCV) infection. Recently, single nucleotide polymorphisms (SNPs) of IL28B and host response to peginterferon α (PEG-IFNα) and ribavirin (RBV) were shown to be strongly associated. We aimed to determine the gene expression involving innate immunity in IL28B genotypes and elucidate its relation to response to antiviral treatment. We genotyped IL28B SNPs (rs8099917 and rs12979860) in 88 chronic hepatitis C patients treated with PEG-IFNα-2b/RBV and quantified expressions of viral sensors (RIG-I, MDA5, and LGP2), adaptor molecule (IPS-1), related ubiquitin E3-ligase (RNF125), modulators (ISG15 and USP18), and IL28 (IFNλ). Both IL28B SNPs were 100% identical; 54 patients possessed rs8099917 TT/rs12979860 CC (IL28B major patients) and 34 possessed rs8099917 TG/rs12979860 CT (IL28B minor patients). Hepatic expressions of viral sensors and modulators in IL28B minor patients were significantly up-regulated compared with that in IL28B major patients (≈ 3.3-fold, P < 0.001). However, expression of IPS-1 was significantly lower in IL28B minor patients (1.2-fold, P = 0.028). Expressions of viral sensors and modulators were significantly higher in nonvirological responders (NVR) than that in others despite stratification by IL28B genotype (≈ 2.6-fold, P < 0.001). Multivariate and ROC analyses indicated that higher RIG-I and ISG15 expressions and RIG-I/IPS-1 expression ratio were independent factors for NVR. IPS-1 down-regulation in IL28B minor patients was confirmed by western blotting, and the extent of IPS-1 protein cleavage was associated with the variable treatment response.
  
  
  CONCLUSIONS
  Gene expression involving innate immunity is strongly associated with IL28B genotype and response to PEG-IFNα/RBV. Both IL28B minor allele and higher RIG-I and ISG15 expressions and RIG-I/IPS-1 ratio are independent factors for NVR.
authors: Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan.
authors: Yasuhiro
authors: Y
authors: Asahina
authors: Kaoru
authors: K
authors: Tsuchiya
authors: Masaru
authors: M
authors: Muraoka
authors: Keisuke
authors: K
authors: Tanaka
authors: Yuichiro
authors: Y
authors: Suzuki
authors: Nobuharu
authors: N
authors: Tamaki
authors: Yoshihide
authors: Y
authors: Hoshioka
authors: Yutaka
authors: Y
authors: Yasui
authors: Tomoji
authors: T
authors: Katoh
authors: Takanori
authors: T
authors: Hosokawa
authors: Ken
authors: K
authors: Ueda
authors: Hiroyuki
authors: H
authors: Nakanishi
authors: Jun
authors: J
authors: Itakura
authors: Yuka
authors: Y
authors: Takahashi
authors: Masayuki
authors: M
authors: Kurosaki
authors: Nobuyuki
authors: N
authors: Enomoto
authors: Sayuri
authors: S
authors: Nitta
authors: Naoya
authors: N
authors: Sakamoto
authors: Namiki
authors: N
authors: Izumi
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000276:immunology; D000368:Aged; D000998:Antiviral Agents / Q000627:therapeutic use; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases / Q000235:genetics / Q000276:immunology; D024882:Drug Resistance, Viral / Q000235:genetics; D005260:Female; D015870:Gene Expression / Q000276:immunology; D020869:Gene Expression Profiling / Q000592:standards; D005838:Genotype; D016174:Hepacivirus / Q000187:drug effects / Q000276:immunology*; D019698:Hepatitis C, Chronic / Q000188:drug therapy / Q000276:immunology*; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics* / Q000276:immunology; D016898:Interferon-alpha / Q000627:therapeutic use; D007372:Interferons; D007378:Interleukins / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism; D008099:Liver / Q000276:immunology / Q000378:metabolism / Q000821:virology; D008297:Male; D008875:Middle Aged; D011092:Polyethylene Glycols / Q000627:therapeutic use; D020641:Polymorphism, Single Nucleotide; D011237:Predictive Value of Tests; D012372:ROC Curve; D011971:Receptors, Immunologic; D012254:Ribavirin / Q000627:therapeutic use; D012680:Sensitivity and Specificity; D000095022:Interferon Lambda
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000998:Antiviral Agents; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases; D016898:Interferon-alpha; D007372:Interferons; D007378:Interleukins; D011092:Polyethylene Glycols; D011971:Receptors, Immunologic; D012254:Ribavirin; C000624353:interferon-lambda, human; D000095022:Interferon Lambda; C505371:MAVS protein, human; C452820:RIGI protein, human