Document Detail


A variant upstream of IFNL3 (IL28B) creating a new interferon gene IFNL4 is associated with impaired clearance of hepatitis C virus.
MedLine Citation:
PMID:  23291588     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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:
Ludmila Prokunina-Olsson; Brian Muchmore; Wei Tang; Ruth M Pfeiffer; Heiyoung Park; Harold Dickensheets; Dianna Hergott; Patricia Porter-Gill; Adam Mumy; Indu Kohaar; Sabrina Chen; Nathan Brand; McAnthony Tarway; Luyang Liu; Faruk Sheikh; Jacquie Astemborski; Herbert L Bonkovsky; Brian R Edlin; Charles D Howell; Timothy R Morgan; David L Thomas; Barbara Rehermann; Raymond P Donnelly; Thomas R O'Brien
Related Documents :
23533588 - Rapid high-level production of functional hiv broadly neutralizing monoclonal antibodie...
23219818 - Pml tumor suppressor protein is required for hcv production.
24797368 - The complexity of hiv persistence and pathogenesis in the lung under antiretroviral the...
25303208 - Hiv testing among clients in high hiv prevalence venues: disparities between older and ...
9665958 - Oral fluids as an alternative to serum for measurement of markers of immune activation.
9620388 - Microscopic examination and broth culture of cerebrospinal fluid in diagnosis of mening...
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, N.I.H., Intramural; Research Support, Non-U.S. Gov't     Date:  2013-01-06
Journal Detail:
Title:  Nature genetics     Volume:  45     ISSN:  1546-1718     ISO Abbreviation:  Nat. Genet.     Publication Date:  2013 Feb 
Date Detail:
Created Date:  2013-01-29     Completed Date:  2013-03-26     Revised Date:  2014-01-20    
Medline Journal Info:
Nlm Unique ID:  9216904     Medline TA:  Nat Genet     Country:  United States    
Other Details:
Languages:  eng     Pagination:  164-71     Citation Subset:  IM    
Export Citation:
APA/MLA Format     Download EndNote     Download BibTex
MeSH Terms
Descriptor/Qualifier:
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
Grant Support
ID/Acronym/Agency:
DA R01 013324/DA/NIDA NIH HHS; N01-CO-12400/CO/NCI NIH HHS; N02-CP-91027/CP/NCI NIH HHS; R01 DA004334/DA/NIDA NIH HHS; R01 DA009532/DA/NIDA NIH HHS; R01 DA012109/DA/NIDA NIH HHS; R01 DA012568/DA/NIDA NIH HHS; R01 DA013245/DA/NIDA NIH HHS; R01 DA013324/DA/NIDA NIH HHS; R01 DA016159/DA/NIDA NIH HHS; R01-DA-04334/DA/NIDA NIH HHS; R01-DA-12568/DA/NIDA NIH HHS; R01-DA09532/DA/NIDA NIH HHS; R01-DA12109/DA/NIDA NIH HHS; R01-DA13245/DA/NIDA NIH HHS; R01-DA16159/DA/NIDA NIH HHS; UL1 TR000153/TR/NCATS NIH HHS
Chemical
Reg. No./Substance:
0/Antibodies, Monoclonal; 0/Genetic Markers; 0/IFNL4 protein, human; 0/Interleukins; 0/STAT1 Transcription Factor; 0/STAT2 Transcription Factor
Comments/Corrections
Comment In:
Nat Rev Gastroenterol Hepatol. 2013 Feb;10(2):63   [PMID:  23338061 ]
Hepatology. 2013 Jul;58(1):439-41   [PMID:  23564545 ]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


Previous Document:  Genome-wide association analysis identifies new susceptibility loci for Behçet's disease and epista...
Next Document:  Genome-wide association analyses identify multiple loci associated with central corneal thickness an...