IL28B expression depends on a novel TT/-G polymorphism which improves HCV clearance prediction

• Published in: The Journal of experimental medicine Vol. 210; no. 6; pp. 1109 - 1116
• Main Authors: Bibert, Stéphanie, Roger, Thierry, Calandra, Thierry, Bochud, Murielle, Cerny, Andreas, Semmo, Nasser, Duong, François H T, Gerlach, Tilman, Malinverni, Raffaele, Moradpour, Darius, Negro, Francesco, Müllhaupt, Beat, Bochud, Pierre-Yves
• Format: Journal Article
• Language: English
• Published: United States The Rockefeller University Press 03.06.2013
• Subjects: Alleles; Brief Definitive Report; Chemokine CXCL10 - biosynthesis; Chemokine CXCL10 - genetics; Chemokine CXCL10 - immunology; Genotype; Hepacivirus - physiology; Hepatitis C virus; Hepatitis C, Chronic - genetics; Hepatitis C, Chronic - immunology; Hepatitis C, Chronic - virology; Humans; Interferon-gamma - biosynthesis; Interferon-gamma - genetics; Interferon-gamma - immunology; Interferons; Interleukins - biosynthesis; Interleukins - genetics; Interleukins - immunology; Leukocytes, Mononuclear - immunology; Leukocytes, Mononuclear - virology; Polymorphism, Genetic; RNA, Messenger - genetics
• ISSN: 0022-1007; 1540-9538
• DOI: 10.1084/jem.20130012

Approximately 3% of the world population is chronically infected with the hepatitis C virus (HCV), with potential development of cirrhosis and hepatocellular carcinoma. Despite the availability of new antiviral agents, treatment remains suboptimal. Genome-wide association studies (GWAS) identified rs12979860, a polymorphism nearby IL28B, as an important predictor of HCV clearance. We report the identification of a novel TT/-G polymorphism in the CpG region upstream of IL28B, which is a better predictor of HCV clearance than rs12979860. By using peripheral blood mononuclear cells (PBMCs) from individuals carrying different allelic combinations of the TT/-G and rs12979860 polymorphisms, we show that induction of IL28B and IFN-γ-inducible protein 10 (IP-10) mRNA relies on TT/-G, but not rs12979860, making TT/-G the only functional variant identified so far. This novel step in understanding the genetic regulation of IL28B may have important implications for clinical practice, as the use of TT/G genotyping instead of rs12979860 would improve patient management.