title: A variant upstream of IFNL3 (IL28B) creating a new interferon gene IFNL4 is associated with impaired clearance of hepatitis C virus.
abstract: Chronic infection with hepatitis C virus (HCV) is a common cause of liver cirrhosis and cancer. We performed RNA sequencing in primary human hepatocytes activated with synthetic double-stranded RNA to mimic HCV infection. 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 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 clearance and its clinical management.
authors.affiliation: Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, US National Institutes of Health, Bethesda, Maryland, USA. prokuninal@mail.nih.gov
authors.forename: Ludmila
authors.initials: L
authors.lastname: Prokunina-Olsson
authors.forename: Brian
authors.initials: B
authors.lastname: Muchmore
authors.forename: Wei
authors.initials: W
authors.lastname: Tang
authors.forename: Ruth M
authors.initials: RM
authors.lastname: Pfeiffer
authors.forename: Heiyoung
authors.initials: H
authors.lastname: Park
authors.forename: Harold
authors.initials: H
authors.lastname: Dickensheets
authors.forename: Dianna
authors.initials: D
authors.lastname: Hergott
authors.forename: Patricia
authors.initials: P
authors.lastname: Porter-Gill
authors.forename: Adam
authors.initials: A
authors.lastname: Mumy
authors.forename: Indu
authors.initials: I
authors.lastname: Kohaar
authors.forename: Sabrina
authors.initials: S
authors.lastname: Chen
authors.forename: Nathan
authors.initials: N
authors.lastname: Brand
authors.forename: McAnthony
authors.initials: M
authors.lastname: Tarway
authors.forename: Luyang
authors.initials: L
authors.lastname: Liu
authors.forename: Faruk
authors.initials: F
authors.lastname: Sheikh
authors.forename: Jacquie
authors.initials: J
authors.lastname: Astemborski
authors.forename: Herbert L
authors.initials: HL
authors.lastname: Bonkovsky
authors.forename: Brian R
authors.initials: BR
authors.lastname: Edlin
authors.forename: Charles D
authors.initials: CD
authors.lastname: Howell
authors.forename: Timothy R
authors.initials: TR
authors.lastname: Morgan
authors.forename: David L
authors.initials: DL
authors.lastname: Thomas
authors.forename: Barbara
authors.initials: B
authors.lastname: Rehermann
authors.forename: Raymond P
authors.initials: RP
authors.lastname: Donnelly
authors.forename: Thomas R
authors.initials: TR
authors.lastname: O'Brien
mesh_terms: D000911:Antibodies, Monoclonal; D002888:Chromosomes, Human, Pair 19 / Q000235:genetics*; D020869:Gene Expression Profiling; D005819:Genetic Markers / Q000235:genetics; D056945:Hep G2 Cells; D006526:Hepatitis C / Q000276:immunology / Q000517:prevention & control*; D006801:Humans; D007378:Interleukins / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D015810:Linkage Disequilibrium; D018613:Microscopy, Confocal; D008954:Models, Biological; D010766:Phosphorylation; D011110:Polymorphism, Genetic / Q000235:genetics*; D050794:STAT1 Transcription Factor / Q000378:metabolism; D050795:STAT2 Transcription Factor / Q000378:metabolism; D017423:Sequence Analysis, RNA; D013045:Species Specificity; D018709:Statistics, Nonparametric; D000095022:Interferon Lambda
chemical_list: D000911:Antibodies, Monoclonal; D005819:Genetic Markers; D007378:Interleukins; D050794:STAT1 Transcription Factor; D050795:STAT2 Transcription Factor; C579163:IFNL4 protein, human; D000095022:Interferon Lambda