Hepatic metallothionein expression in chronic hepatitis C virus infection is IFNL3 genotype-dependent

• Published in: Genes and immunity Vol. 15; no. 2; pp. 88 - 94
• Main Authors: O'Connor, K S, Parnell, G, Patrick, E, Ahlenstiel, G, Suppiah, V, van der Poorten, D, Read, S A, Leung, R, Douglas, M W, Yang, J YH, Stewart, G J, Liddle, C, George, J, Booth, D R
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.03.2014; Nature Publishing Group
• Subjects: 631/250/127/1212; 631/250/2502/248; 692/699/255/234/2513/1551; 692/700/565; Biomedical and Life Sciences; Biomedicine; Biopsy; Cancer Research; Chronic infection; Fibrosis; Gene Expression; Genes; Genetic aspects; Genomes; Genotype; Genotype & phenotype; Genotypes; Hepacivirus; Hepatitis C; Hepatitis C virus; Hepatitis C, Chronic - drug therapy; Human Genetics; Humans; Immune clearance; Immunology; Infections; Interferon; Interferon alpha; Interferon Regulatory Factors - genetics; Interferon-alpha - therapeutic use; Interferons; Interleukins - genetics; Liver; Liver - pathology; Liver - virology; Liver Cirrhosis - genetics; Metallothionein; Metallothionein - biosynthesis; original-article; Peripheral blood; Physiological aspects; Polyethylene Glycols - therapeutic use; Polymorphism, Single Nucleotide; Recombinant Proteins - therapeutic use; Ribavirin - therapeutic use; Treatment Outcome; Up-Regulation; Viral Load - genetics; Australia; New South Wales Australia; hepatitis C virus; metallothioneins; interferon-stimulated genes; IFNL3
• ISSN: 1466-4879; 1476-5470; 1476-5470
• DOI: 10.1038/gene.2013.66

The IFNL3 genotype predicts the clearance of hepatitis C virus (HCV), spontaneously and with interferon (IFN)-based therapy. The responder genotype is associated with lower expression of interferon stimulated genes (ISGs) in liver biopsies from chronic hepatitis C patients. However, ISGs represent many interacting molecular pathways, and we hypothesised that the IFNL3 genotype may produce a characteristic pattern of ISG expression explaining the effect of genotype on viral clearance. For the first time, we identified an association between a cluster of ISGs, the metallothioneins (MTs) and IFNL3 genotype. Importantly, MTs were significantly upregulated (in contrast to most other ISGs) in HCV-infected liver biopsies of rs8099917 responders. An association between lower fibrosis scores and higher MT levels was demonstrated underlying clinical relevance of this association. As expected, overall ISGs were significantly downregulated in biopsies from subjects with the IFNL3 rs8099917 responder genotype ( P =2.38 × 10 −7 ). Peripheral blood analysis revealed paradoxical and not previously described findings with upregulation of ISGs seen in the responder genotype ( P =1.00 × 10 −4 ). The higher MT expression in responders may contribute to their improved viral clearance and MT-inducing agents may be useful adjuncts to therapy for HCV. Upregulation of immune cell ISGs in responders may also contribute to the IFNL3 genotype effect.