Upstream of IFNL3 (IL28B) on chromosome 19q13.13, we discovered a new transiently induced region that harbors a dinucleotide variant ss469415590 (TT or δG), which is in high linkage

disequilibrium with rs12979860, a genetic marker strongly associated with HCV clearance. ss469415590[δG] is a frameshift variant that creates a novel gene, designated IFNL4, encoding MK-1775 price the interferon-λ4 protein (IFNL4), which is moderately similar to IFNL3. Compared to rs12979860, ss469415590 is more strongly associated with HCV clearance in individuals of African ancestry, although it provides comparable information in Europeans and Asians. Transient overexpression of IFNL4 in a hepatoma cell line induced STAT1 and STAT2 phosphorylation and the expression of interferon-stimulated genes. Our findings provide new insights into the genetic regulation of HCV find more clearance and its clinical management. Interferons alpha (IFN-β) and lambda (IFNL) are cytokines with key roles in combating viral infections. Engagement of IFN receptor complexes results in JAK/STAT (Janus kinase / signal transducers and activators of transcription) signaling that induces the expression of hundreds of interferon-stimulated genes (ISGs) as part of an elaborate host cell defense program adapted to combat infections.1 Pegylated IFN-β (PEG-IFN-β) in combination with ribavirin is

part of the standard-of-care (SOC) treatment for chronic hepatitis C (CHC). However, treatment response is variable and dependent on several host factors including gender and race.2 For example, SOC therapy is less effective in treating African Americans (AA) than Caucasian Americans.3 Furthermore, several studies demonstrated that patients with delayed or nonresponse to IFN-β treatment have higher expression levels of ISGs prior to therapy than those successfully treated.4–6 This is likely due to a preactivated refractory state of the IFN signaling pathway.7 Previous genome-wide association studies of CHC patients have identified single nucleotide

polymorphisms (SNPs) in the region of the IFNL3 (IL28B, IFN-l3) gene on chromosome 19q13.13 that correlate with both spontaneous,8, 9 and IFN-mediated HCV clearance,9–12 and could act as a predictive biomarker for SOC efficacy.13 Furthermore, other markers have been medchemexpress proposed to play a role in viral clearance.14, 15 One of these SNPs in the IFNL3 region at position 12979860 (rs12979860) has been linked both to hepatic ISG expression and outcome of IFN therapy for CHC.16 Although many studies have investigated the functional role of this SNP, its associated pathogenetic mechanisms remain poorly understood.17 In this context, a recent multicenter study by Prokunina-Olsson et al. identified a novel SNP at position 469415590 (ss469415590 (TT or δG)) upstream of the IFNL3 gene with potential relevance for viral pathogenesis and treatment response.