Toll-like receptor 7 rs179008/Gln11Leu gene variants in chronic hepatitis C virus infection

Abstract

Hepatitis C virus (HCV) infection affects an estimated 3% of the world's population. The natural outcome of infection and the natural course of disease are highly variable. Sensing of viral single-stranded RNA (ssRNA) by Toll-like receptor 7 (TLR7) is likely involved in early pathogen detection and host response to viral infections. This study analyzed epidemiological and clinical data from 136 patients with HCV infection with regard to rs179008/Gln11Leu, a non-synonymous polymorphism within exon 3 of the X-linked TLR7 gene, the variant allele of which is suggested to code for a functionally impaired protein. Allele-specific transcript quantification (ASTQ) analyses in heterozygous females revealed individual skewed mosaicism in peripheral blood mononuclear cells (PBMCs). Thus, analyses were restricted to homo- and hemizygous individuals. Among the clinical and histological parameters studied, the variant allele T was found to be solely associated with the presence of portal lymphoid aggregates. Whereas hepatic viral load and expression of genes known to be induced in chronic HCV infection were not found to differ in patients with wild-type or variant TLR7 rs179008 genotype, significant lower gene expression of interleukin-29 (IL-29)/lambda1 interferon (IFN-λ1) and both of its receptor subunits was found for T homo- and hemizygous patients. Irrespective of the minor differences in disease phenotype including hepatic viral load, natural, and alpha interferon (IFN-α)-mediated outcome of infection, and disease activity and progression, the significant differences in hepatic IL-29/IFN-λ1 and IFN-λ receptor gene expression between TLR7 rs179008 T and A allele patients might have implications for responsiveness to future IFN-λ-based approaches. J. Med. Virol. 82:1859-1868, 2010. © 2010 Wiley-Liss, Inc.