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

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. MorganDavid L Thomas, Barbara Rehermann, Raymond P. Donnelly, Thomas R. O'Brien

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)164-171
Number of pages8
JournalNature Genetics
Volume45
Issue number2
DOIs
StatePublished - Feb 2013

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Hepacivirus
Interferons
Genes
RNA Sequence Analysis
Double-Stranded RNA
Linkage Disequilibrium
Virus Diseases
Liver Neoplasms
Genetic Markers
Liver Cirrhosis
Hepatocytes
Hepatocellular Carcinoma
Chromosomes
Phosphorylation
Cell Line
Infection
Proteins

ASJC Scopus subject areas

  • Genetics

Cite this

Prokunina-Olsson, L., Muchmore, B., Tang, W., Pfeiffer, R. M., Park, H., Dickensheets, H., ... O'Brien, T. R. (2013). A variant upstream of IFNL3 (IL28B) creating a new interferon gene IFNL4 is associated with impaired clearance of hepatitis C virus. Nature Genetics, 45(2), 164-171. https://doi.org/10.1038/ng.2521

A variant upstream of IFNL3 (IL28B) creating a new interferon gene IFNL4 is associated with impaired clearance of hepatitis C virus. / Prokunina-Olsson, Ludmila; 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.

In: Nature Genetics, Vol. 45, No. 2, 02.2013, p. 164-171.

Research output: Contribution to journalArticle

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 2013, '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, pp. 164-171. https://doi.org/10.1038/ng.2521
Prokunina-Olsson, Ludmila ; 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. / A variant upstream of IFNL3 (IL28B) creating a new interferon gene IFNL4 is associated with impaired clearance of hepatitis C virus. In: Nature Genetics. 2013 ; Vol. 45, No. 2. pp. 164-171.
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