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Type: Journal article
Title: A novel I-TAC promoter polymorphic variant is functional in the presence of replicating HCV in vitro
Author: Helbig, K.
George, J.
Beard, M.
Citation: Journal of Clinical Virology, 2005; 32(2):137-143
Publisher: Elsevier Science BV
Issue Date: 2005
ISSN: 1386-6532
Abstract: BACKGROUND: Chemokines are strong candidate genes for outcome of HCV infection. I-TAC is a chemokine known to be involved in the inflammatory process of HCV infection, and its expression is upregulated in chronic hepatitis C (CHC). OBJECTIVES: The aim of this study was to investigate genetic variability in the I-TAC promoter and to determine the correlation of these variants with HCV disease progression. STUDY DESIGN: I-TAC genotyping was performed in 60 chronic HCV patients and 60 controls using GeneScan analysis. Functional analysis of the I-TAC promoter was performed with the aid of luciferase reporter constructs transfected into Huh-7 cells or Huh-7 cells harbouring HCV genomic and sub-genomic replicons. Cytokine induced production of I-TAC from whole blood cultures was measured using enzyme-linked immunosorbent assay (ELISA). RESULTS: Sequencing of approximately 1 kb upstream of the I-TAC gene start codon revealed the presence of a novel 5 bp deletion mutant (-599del5) in a number of chronic HCV patients. Analysis of the functional potential of this deletion revealed no transcriptional change in Huh-7 cells transfected with luciferase reporter constructs, and this was confirmed in cytokine stimulated whole blood cultures where similar levels of I-TAC were liberated regardless of -599del5 genotype. Conversely, the -599del5 deletion variant significantly reduced transcriptional activity of the I-TAC promoter in the presence of replicating HCV. The distribution frequency of the allele was found to be significantly increased in a chronically HCV infected population compared to healthy controls. CONCLUSIONS: The novel I-TAC -599del5 promoter polymorphism is a functional variant in the presence of replicating HCV. Furthermore, this deletion mutant is significantly increased in a chronic HCV cohort and may predispose to HCV disease susceptibility.
Keywords: HCV; I-TAC; Polymorphism; Promoter
Rights: Copyright © 2004 Elsevier B.V. All rights reserved.
RMID: 0020050118
DOI: 10.1016/j.jcv.2004.10.001
Appears in Collections:Molecular and Biomedical Science publications

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