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PMID: 23291588 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, N.I.H., Intramural Research Support, Non-U.S. Gov't

A variant upstream of IFNL3 (IL28B) creating a new interferon gene IFNL4 is associated with impaired clearance of hepatitis C virus.

Nature genetics ·Vol. 45 ·No. 2 ·2013-02-00 ·Pages 164-71

Prokunina-Olsson L, Muchmore B, Tang W, Pfeiffer RM, Park H, Dickensheets H, Hergott D, Porter-Gill P, Mumy A, Kohaar I, Chen S, Brand N, Tarway M, Liu L, Sheikh F, Astemborski J, Bonkovsky HL, Edlin BR, Howell CD, Morgan TR, Thomas DL, Rehermann B, Donnelly RP, O'Brien TR

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.

MeSH Terms
Antibodies, Monoclonal Chromosomes, Human, Pair 19/genetics Gene Expression Profiling Genetic Markers/genetics Hep G2 Cells Hepatitis C/immunology,prevention & control Humans Interleukins/genetics,immunology,metabolism Linkage Disequilibrium Microscopy, Confocal Models, Biological Phosphorylation Polymorphism, Genetic/genetics STAT1 Transcription Factor/metabolism STAT2 Transcription Factor/metabolism Sequence Analysis, RNA Species Specificity Statistics, Nonparametric
Chemicals
Antibodies, Monoclonal Genetic Markers IFNL4 protein, human Interleukins STAT1 Transcription Factor STAT2 Transcription Factor
Authors & Affiliations
24 authors, click to expand affiliations / ORCID
Prokunina-Olsson Ludmila
Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, US National Institutes of Health, Bethesda, Maryland, USA. [email protected]
Muchmore Brian
Tang Wei
Pfeiffer Ruth M
Park Heiyoung
Dickensheets Harold
Hergott Dianna
Porter-Gill Patricia
Mumy Adam
Kohaar Indu
Chen Sabrina
Brand Nathan
Tarway McAnthony
Liu Luyang
Sheikh Faruk
Astemborski Jacquie
Bonkovsky Herbert L
Edlin Brian R
Howell Charles D
Morgan Timothy R
Thomas David L
Rehermann Barbara
Donnelly Raymond P
O'Brien Thomas R
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Article Info
Journal
Nature genetics
Abbr.
Nat Genet
ISSN
1546-1718
DOI
10.1038/ng.2521
Email
[email protected]
Published
2013-02-00
Epub
2013-00-06
Pages
164-71
Language
English
Region
United States
NLM ID
9216904
PMCID
PMC3793390
Subset
IM
Grants
NIDA NIH HHS · R01-DA-12568 · United States
NIDA NIH HHS · DA R01 013324 · United States
NIDA NIH HHS · R01 DA012109 · United States
NIDA NIH HHS · R01 DA004334 · United States
NIDA NIH HHS · R01 DA009532 · United States
NIDA NIH HHS · R01 DA016159 · United States
NIDA NIH HHS · R01-DA13245 · United States
Intramural NIH HHS · United States
NCI NIH HHS · N01CO12400 · United States
NIDA NIH HHS · R01-DA-04334 · United States
NIDA NIH HHS · U01 DA036297 · United States
NIDA NIH HHS · R01-DA16159 · United States
NIDA NIH HHS · R01 DA013245 · United States
NIDA NIH HHS · R01 DA013324 · United States
NIDA NIH HHS · R01-DA09532 · United States
NIDA NIH HHS · R01 DA012568 · United States
NCI NIH HHS · N01-CO-12400 · United States
NCI NIH HHS · N02-CP-91027 · United States
Corrections
CommentIn
PMID: 23338061
CommentIn
PMID: 23564545
External Links
PubMed source DOI: 10.1038/ng.2521 PMC Full Text View journal details
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