title: IL28 variation affects expression of interferon stimulated genes and peg-interferon and ribavirin therapy.
abstract: OBJECTIVE
  Common genetic variation within the IL28 locus has been found to influence the effect of peg-interferon and ribavirin combination therapy against chronic hepatitis C virus (HCV) infection. Expression of IL28 in peripheral blood cells has been reported to be higher in patients with IL28 SNP genotypes associated with favorable response.
  
  
  METHODS
  We analyzed 52 liver and 114 blood samples obtained from patients with HCV genotype 1b. We used reverse transcription-real time polymerase chain reaction to analyze expression levels of IL28 and several interferon stimulated genes (ISGs), including MxA, double stranded RNA dependent protein kinase (PKR), 2'-5' oligo-nucleotide synthetase (OAS1), ISG15, and SOCS1.
  
  
  RESULTS
  Interestingly, expression of IL28 was significantly lower in patients with the response-favorable rs8099917 TT genotype compared to those with TG or GG genotypes (p<0.005). In hepatic cells, expression of MxA, PKR, OAS1, and ISG15 were also significantly lower in rs8099917 TT patients (p<0.001, p=0.005, p=0.001, p<0.001, respectively), whereas in peripheral blood mononuclear cells ISG expression levels did not differ significantly. Among patients treated with peg-interferon plus ribavirin therapy, liver mRNA levels of IL28, MxA, PKR, OAS1, and ISG15 were significantly or marginally lower in responders who became negative for HCV RNA (p=0.001, 0.004, 0.014, 0.051, and 0.015, respectively).
  
  
  CONCLUSIONS
  Expression levels of ISGs are differentially regulated in the liver and peripheral blood. The mechanism underlying the expression levels of IL28 and ISGs and the correlation with the effect of the therapy should be further investigated.
authors.affiliation: Laboratory for Digestive Diseases, Center for Genomic Medicine, RIKEN, Hiroshima, Japan.
authors.forename: Hiromi
authors.initials: H
authors.lastname: Abe
authors.forename: C Nelson
authors.initials: CN
authors.lastname: Hayes
authors.forename: Hidenori
authors.initials: H
authors.lastname: Ochi
authors.forename: Toshiro
authors.initials: T
authors.lastname: Maekawa
authors.forename: Masataka
authors.initials: M
authors.lastname: Tsuge
authors.forename: Daiki
authors.initials: D
authors.lastname: Miki
authors.forename: Fukiko
authors.initials: F
authors.lastname: Mitsui
authors.forename: Nobuhiko
authors.initials: N
authors.lastname: Hiraga
authors.forename: Michio
authors.initials: M
authors.lastname: Imamura
authors.forename: Shoichi
authors.initials: S
authors.lastname: Takahashi
authors.forename: Michiaki
authors.initials: M
authors.lastname: Kubo
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Nakamura
authors.forename: Kazuaki
authors.initials: K
authors.lastname: Chayama
mesh_terms: D015088:2',5'-Oligoadenylate Synthetase / Q000235:genetics; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000998:Antiviral Agents / Q000008:administration & dosage*; D016207:Cytokines / Q000235:genetics; D004359:Drug Therapy, Combination; D005260:Female; D019204:GTP-Binding Proteins / Q000235:genetics; D015870:Gene Expression; D016174:Hepacivirus / Q000235:genetics; D019698:Hepatitis C, Chronic / Q000188:drug therapy* / Q000235:genetics* / Q000276:immunology / Q000821:virology; D006801:Humans; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000008:administration & dosage*; D007372:Interferons; D007378:Interleukins / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D064547:Myxovirus Resistance Proteins; D011092:Polyethylene Glycols / Q000008:administration & dosage*; D020641:Polymorphism, Single Nucleotide; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins; D012254:Ribavirin / Q000008:administration & dosage*; D016896:Treatment Outcome; D014452:Ubiquitins / Q000235:genetics; D019892:eIF-2 Kinase / Q000235:genetics; D000095022:Interferon Lambda
chemical_list: D015088:2',5'-Oligoadenylate Synthetase; D000998:Antiviral Agents; D016207:Cytokines; D019204:GTP-Binding Proteins; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D007372:Interferons; D007378:Interleukins; D064547:Myxovirus Resistance Proteins; D011092:Polyethylene Glycols; D012333:RNA, Messenger; D011994:Recombinant Proteins; D012254:Ribavirin; D014452:Ubiquitins; D019892:eIF-2 Kinase; C000624353:interferon-lambda, human; D000095022:Interferon Lambda; C579071:MX1 protein, human; C074034:ISG15 protein, human; C475085:OAS1 protein, human; C417083:peginterferon alfa-2b