title: Epigenetic analysis of the IFNλ3 gene identifies a novel marker for response to therapy in HCV-infected subjects.
abstract: Chronic hepatitis C virus (HCV) infection is characterized by high interindividual variability in response to pegylated interferon and ribavirin. A genetic polymorphism on chromosome 19 (rs12979860) upstream of interferon-λ3 (IFNλ3) is associated with a twofold change in sustained virologic response rate after 48 weeks of treatment with pegylated interferon/ribavirin in HCV genotype 1 (GT1) treatment-naïve patients. We conducted epigenetic analysis on the IFNλ3 promoter to investigate whether DNA methylation is associated with response to HCV therapy. DNA samples from HCV GT1-infected subjects receiving an interferon-free paritaprevir-containing combination regimen (N=540) and from HCV-uninfected, healthy controls (N=124) were analysed for IFNλ3 methylation levels. Methylation was strongly associated with rs12979860 allele status whether adjusting for HCV status (r=65.0%, 95% CI: [60.2%, 69.5%]), or not (r=64.4%), both with P<2.2×10-16. In HCV GT1-infected subjects, C/C genotypes had significantly lower methylation levels relative to C/T or T/T genotypes (P<1×10-14), with each T allele resulting in a nine-unit increase in mean methylation level. Methylation levels did not correlate with response in subjects treated for 12 or 24 weeks. However, non-C/C subjects with higher methylation levels were more likely to relapse when treatment duration was 8 weeks. This analysis suggests that methylation status of the IFNλ3 promoter region may be a useful parameter that identifies patients more likely to relapse following HCV therapy; however, continuing therapy for a sufficient duration can overcome this difference. These findings may provide mechanistic insight into the role of IFNλ3 genetic variants in HCV treatment response.
authors.affiliation: AbbVie Inc., North Chicago, IL, USA.
authors.forename: J F
authors.initials: JF
authors.lastname: Waring
authors.affiliation: AbbVie Inc., North Chicago, IL, USA.
authors.forename: J W
authors.initials: JW
authors.lastname: Davis
authors.affiliation: AbbVie Inc., North Chicago, IL, USA.
authors.forename: E
authors.initials: E
authors.lastname: Dumas
authors.affiliation: AbbVie Inc., North Chicago, IL, USA.
authors.forename: D
authors.initials: D
authors.lastname: Cohen
authors.affiliation: AbbVie Inc., North Chicago, IL, USA.
authors.forename: K
authors.initials: K
authors.lastname: Idler
authors.affiliation: AbbVie Inc., North Chicago, IL, USA.
authors.forename: S
authors.initials: S
authors.lastname: Abel
authors.affiliation: AbbVie Inc., North Chicago, IL, USA.
authors.forename: R
authors.initials: R
authors.lastname: Georgantas
authors.affiliation: AbbVie Inc., North Chicago, IL, USA.
authors.forename: T
authors.initials: T
authors.lastname: Podsadecki
authors.affiliation: AbbVie Inc., North Chicago, IL, USA.
authors.forename: S
authors.initials: S
authors.lastname: Dutta
mesh_terms: D000483:Alleles; D000998:Antiviral Agents / Q000627:therapeutic use*; D003521:Cyclopropanes; D019175:DNA Methylation; D004359:Drug Therapy, Combination; D044127:Epigenesis, Genetic; D005260:Female; D005819:Genetic Markers; D019698:Hepatitis C, Chronic / Q000188:drug therapy* / Q000473:pathology*; D006801:Humans; D007372:Interferons; D007378:Interleukins / Q000235:genetics*; D047029:Lactams, Macrocyclic; D047028:Macrocyclic Compounds / Q000627:therapeutic use; D008297:Male; D020641:Polymorphism, Single Nucleotide; D011392:Proline / Q000031:analogs & derivatives; D011401:Promoter Regions, Genetic; D012008:Recurrence; D013449:Sulfonamides; D017211:Treatment Failure; D000095022:Interferon Lambda
chemical_list: D000998:Antiviral Agents; D003521:Cyclopropanes; D005819:Genetic Markers; D007372:Interferons; D007378:Interleukins; D047029:Lactams, Macrocyclic; D047028:Macrocyclic Compounds; D011392:Proline; D013449:Sulfonamides; C000624353:interferon-lambda, human; D000095022:Interferon Lambda; C585405:paritaprevir
keywords: HCV; IFNλ3; dasabuvir; methylation; ombitasvir; paritaprevir