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

• DOI: 10.1084/jem.20130012
• Publication Date: 2013-05-28T01:00:41Z
• Authors: Stéphanie Bibert; Thierry Roger; Thierry Calandra; Murielle Bochud; Andreas Cerny; Nasser Semmo; François H.T. Duong; Tilman Gerlach; Raffaele Malinverni; Darius Moradpour; Francesco Negro; Beat Müllhaupt; Pierre-Yves Bochud
• Keywords: ddc:616; 0301 basic medicine; 2403 Immunology; Polymorphism, Genetic; Genotype; info:eu-repo/classification/ddc/616.07; Interleukins; Brief Definitive Report; 610 Medicine & health; Hepacivirus; ddc:616.07; Hepatitis C, Chronic; 3. Good health; Chemokine CXCL10; Interferon-gamma; 03 medical and health sciences; 10219 Clinic for Gastroenterology and Hepatology; info:eu-repo/classification/ddc/616; 2723 Immunology and Allergy; Leukocytes, Mononuclear; Humans; Interferons; RNA, Messenger; Alleles

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.