Inverse Association of IL28B Genotype and Liver mRNA Expression of Genes Promoting or Suppressing Antiviral State

High intrahepatic expression levels of interferon stimulated genes (ISGs) in chronic hepatitis C patients are associated with poor response to interferon plus ribavirin combination therapy. Expression levels of 16 genes (OAS1, PKR, MxA, ISG15, RIG-I, TLR8, IRF7, IRF9, NFKBIA, IL28A/IL28B, IL29, IL28RA, IL10RB, IFNAR2, and STAT1) that promote antiviral state and 4 genes (SOCS1, SOCS3, Zc3h12a, and A20) that suppress antiviral state were analyzed using real-time PCR assays in 133 liver biopsy samples from patients infected with genotypes 1 or 2. Expression levels of genes promoting antiviral state were positively correlated with each other but were not correlated with those that suppress antiviral state. Expression levels of some ISGs were inversely associated with common polymorphisms within the IL28B locus. Genes promoting antiviral state were expressed lower (e. g., ISG15, P = 1.42E-12 and MxA, P = 6.40E-11) in individuals with the protective rs12979860 CC genotype, and genes suppressing antiviral state were expressed higher (A20, P = 0.00107 and Zc3h12a, P = 0.00129, respectively), although some ISGs were not significant after the Bonferroni correction. The expression levels of both an antiviral (MxA) and a suppressor (SOCS1) ISG were independent predictors for non-response. These results suggest that rs12979860 genotype may be associated with response to combination therapy through an inverse relationship between antiviral and suppressor ISGs in the liver. J. Med. Virol. 83: 1597-1607, 2011. (C) 2011 Wiley-Liss, Inc.