title: Hepatic expression levels of interferons and interferon-stimulated genes in patients with chronic hepatitis C: A phenotype-genotype correlation study.
abstract: IFNL4 is linked to hepatitis C virus treatment response and type III interferons (IFNs). We studied the functional associations among hepatic expressions of IFNs and IFN-stimulated genes (ISGs), and treatment response to peginterferon and ribavirin. Type I IFNs (IFNA1, IFNB1), type II (IFNG), type III (IFNL1, IFNL2/3), IFNL4 and ISG hepatic expressions were measured by qPCR from in 65 chronic hepatitis C (CHC) patients whose IFNL4-associated rs368234815 and IFNL3-associated rs12989760 genotype were determined. There was a robust correlation of hepatic expression within type I and type III IFNs and between type III IFNs and IFNL4 but no correlation between other IFN types. Expression of ISGs correlated with type III IFNs and IFNL4 but not with type I IFNs. Levels of ISGs and IFNL2/3 mRNAs were lower in IFNL3 rs12979860 CC patients compared with non-CC patients, and in treatment responders, compared with nonresponders. IFNL4-ΔG genotype was associated with high ISG levels and nonresponse. Hepatic levels of ISGs in CHC are associated with IFNL2/3 and IFNL4 expression, suggesting that IFNLs, not other types of IFNs, drive ISG expression. Hepatic IFNL2/3 expression is functionally linked to IFNL4 and IFNL3 polymorphisms, potentially explaining the tight association among ISG expression and treatment response.
authors.affiliation: 1] Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA [2] Division of Gastroenterology, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
authors.forename: M
authors.initials: M
authors.lastname: Noureddin
authors.affiliation: Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Rotman
authors.affiliation: Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA.
authors.forename: F
authors.initials: F
authors.lastname: Zhang
authors.affiliation: 1] Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA [2] Immunology Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA.
authors.forename: H
authors.initials: H
authors.lastname: Park
authors.affiliation: 1] Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA [2] Immunology Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA.
authors.forename: B
authors.initials: B
authors.lastname: Rehermann
authors.affiliation: Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA.
authors.forename: E
authors.initials: E
authors.lastname: Thomas
authors.affiliation: Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA.
authors.forename: T J
authors.initials: TJ
authors.lastname: Liang
mesh_terms: D000328:Adult; D000998:Antiviral Agents / Q000494:pharmacology / Q000627:therapeutic use; D005260:Female; D005838:Genotype; D019698:Hepatitis C, Chronic / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D050835:Interferon Regulatory Factors / Q000235:genetics* / Q000378:metabolism; D007372:Interferons / Q000235:genetics* / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D012254:Ribavirin / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D000998:Antiviral Agents; D050835:Interferon Regulatory Factors; D012254:Ribavirin; D007372:Interferons