Background/aims Genetic variation of the IL28B gene region has beenassociated with a 2-fold increase in SVR rate in chronic hepatitis C (CHC)patients treated with peginterferon-α (pegIFN) and ribavirin (RBV). Theunderlying mechanism remains unclear. We hypothesized that IL28Bpolymorphism is associated with intrahepatic expression levels of IFNstimulatedgenes (ISGs), known to infl uence treatment outcome.Methods 74 CHC patients with consent for genetic testing and storedliver tissue were identifi ed. 48 were treatment-naïve, 26 were nonresponders(NR) to prior IFN therapy (off-treatment for = 6 months priorto biopsy). "IL28B-type" (rs12979860: CC, CT, TT) was tested using theABI TaqMan allelic discrimination kit. Whole-genome expression datawas measured using the Illumina HumanHT-12 Expression BeadChip anddifferences in gene expression by IL28B-type (CC vs non-CC) were analyzedusing Partek and Ingenuity Pathway Analysis, adjusting for HCVgenotype, gender, age and ethnicity. To declare signifi cance, we used afalse discovery rate (FDR) threshold of 0.1.Results Data from 61 patients were suitable for analysis: HCV-1 = 90%;male = 67%; median age = 52 years; ethnicity = 62% Caucasian, 20%African American, 18% other; 70% were METAVIR F0-2, none cirrhotic.In the comparison of differential intrahepatic mRNA expression, 164genes were signifi cant. ISGs were heavily over-represented and showedlower expression levels in CC livers (OAS 1/2/3, MX1, IFIT 1/2/3 andISG15 all had > 3-fold lower expression). IL28B and IL28A gene expressionwere detectable at low levels; there was no difference by IL28B-type.The IFN signaling pathway was the most enriched canonical pathwaydifferentially expressed by IL28B-type (P-value < 10-5). In 25 patientsPEG/RBV response data was available (17 were NR prior to biopsy; 5/8treated post-biopsy attained SVR). IL28B-type was strongly associatedwith SVR (P-value = 0.004). SVR was associated with lower intrahepaticISG expression levels.Conclusions The CC IL28B-type was strongly associated with reducedexpression of intrahepatic ISGs. In a subset, SVR was associated withboth CC IL28B-type and reduced ISG expression. This suggests thatgenetic variation in IL28B regulates the innate immune response to HCVin the liver, priming patients for a stronger ISG response to exogenousIFN therapy.