title: Inverse association of IL28B genotype and liver mRNA expression of genes promoting or suppressing antiviral state.
abstract: 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.
authors: Laboratory for Digestive Diseases, Center for Genomic Medicine, RIKEN, Hiroshima, Japan.
authors: Hiromi
authors: H
authors: Abe
authors: C Nelson
authors: CN
authors: Hayes
authors: Hidenori
authors: H
authors: Ochi
authors: Masataka
authors: M
authors: Tsuge
authors: Daiki
authors: D
authors: Miki
authors: Nobuhiko
authors: N
authors: Hiraga
authors: Michio
authors: M
authors: Imamura
authors: Shoichi
authors: S
authors: Takahashi
authors: Michiaki
authors: M
authors: Kubo
authors: Yusuke
authors: Y
authors: Nakamura
authors: Naoyuki
authors: N
authors: Kamatani
authors: Kazuaki
authors: K
authors: Chayama
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000998:Antiviral Agents / Q000627:therapeutic use; D004359:Drug Therapy, Combination; D005260:Female; D015870:Gene Expression; D005838:Genotype; D016174:Hepacivirus / Q000187:drug effects; D019698:Hepatitis C, Chronic / Q000188:drug therapy / Q000235:genetics* / Q000821:virology; D006801:Humans; D007372:Interferons / Q000627:therapeutic use; D007378:Interleukins / Q000096:biosynthesis / Q000235:genetics*; D008099:Liver / Q000166:cytology / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012254:Ribavirin / Q000627:therapeutic use; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics*; D017211:Treatment Failure; D000095022:Interferon Lambda
chemical_list: D000998:Antiviral Agents; D007372:Interferons; D007378:Interleukins; D012333:RNA, Messenger; D012254:Ribavirin; D050826:Suppressor of Cytokine Signaling Proteins; C000624353:interferon-lambda, human; D000095022:Interferon Lambda