Association of TLR7 single nucleotide polymorphisms with chronic HCV‐infection and response to interferon‐a‐based therapy

Abstract

An efficient immune response against hepatitis C virus (HCV) is necessary to clear infection. As HCV is a single-stranded RNA virus, a role for TLR7 in the immune response against HCV is possible, and early clinical studies have demonstrated an antiviral effect of TLR7 stimulation. We tested the hypothesis that genetic variations of TLR7 are associated with chronic HCV-infection and outcome of therapy. The prevalence of three TLR7 variations was analysed in 978 patients with chronic HCV-infection, 898 patients with chronic liver disease of other aetiologies, and in 203 healthy controls. The prevalence of TLR7 variations was correlated with the response to interferon-alpha-based treatment in 544 patients with chronic HCV-infection. We analysed TLR7 polymorphisms by melting curve analysis and reconstructed haplotypes. The c.32A>T variation was over-represented in female patients with chronic HCV-infection compared to patients with other chronic liver diseases and to healthy controls (P < 0.05). In contrast, c.2403 G>A was less prevalent in male patients with chronic HCV-infection (P < 0.05). No association was observed for the third variant, c.1-120T>G. Haplotype analysis confirmed the differential distribution of TLR7 variants between the groups. Within the group of female patients with chronic HCV-infection, c.32T was predictive of an unfavourable outcome of interferon-alpha therapy (P < 0.05). This study reports the association of TLR7 variants with chronic HCV-infection and with the response to interferon-alpha therapy in patients with chronic HCV-infection. Our results suggest that variations of TLR7 impair the immune response to HCV and imply a gender-specific effect of this X-chromosomal variation.

TLR7 polymorphism, sex and chronic HBV infection influence plasmacytoid DC maturation by TLR7 ligands

“…These are the only reported effects of the SNP at the protein/cellular level and these data were mostly (for livers), or completely (for pDCs), derived from hemizygous males. As stated above, however, most reported clinical effects of the SNP are observed in females (Oh et al, 2009;Schott et al, 2007b). We also identified effects of the SNP only in females.…”

“…In both infections, the variant allele associated with higher disease prevalence and augmented disease progression, and with reduced response to IFNα-therapy for HCV (Oh et al, 2009;Said et al, 2014;Askar et al, 2010;Schott et al, 2007b;Fakhir et al, 2018). In all these studies, effects were most prominent in (mostly rs179008 heterozygous) females and all studies predominantly contained Caucasian individuals.…”

Genetic Variation of Host Immune Response Genes and Their Effect on Hepatitis C Infection and Treatment Outcome

“…Variations in TLR7 and some ISGs have been shown to be associated with HCV infection outcome (reviewed in (Rauch, Gaudieri et al 2009). One such study has shown the association between variations within TLR 7 and HCV infection outcome (Schott, Witt et al 2008). In this study, variants at position 32 and 2403 of TLR7 were associated with viral persistence and IFN- treatment outcome.…”

“…Underlined HLA alleles appear in more than one study. References: (Thio, Gao et al 2002;McKiernan, Hagan et al 2004;Wang, Zheng et al 2009), (Thio, Thomas et al 2001;Yee 2004;Yoon, Han et al 2005;Ksiaa, Ayed-Jendoubi et al 2007;Harris, Sugimoto et al 2008), (Ishida, Ikebuchi et al 2011), (Falleti, Fabris et al 2010), (Haas, Weiß et al 2009), (Mueller, Mas-Marques et al 2004), (Yee, Tang et al 2001) (Morgan, Lambrecht et al 2008), (Thio, Goedert et al 2004;Paladino, Fainboim et al 2006), (Knapp, Hennig et al 2003;Lio, Caruso et al 2003;Kimura, Saito et al 2006;An, Thio et al 2008), (Schott, Witt et al 2008), (Huang, Yang et al 2007), (Ge, Fellay et al 2009;Mangia, Thompson et al 2010), (Tanaka, Nishida et al 2009;Rauch, Kutalik et al 2010), (Vejbaesya, Nonnoi et al 2011), (Khakoo, Thio et al 2004;Montes-Cano, Caro-Oleas et al 2005), (Persico, Capasso et al 2008), (Su, Yee et al 2008), (Suzuki, Arase et al 2004), (Knapp, Yee et al 2003), (Dai, Chuang et al 2010). The innate immune system has a critical role in detecting pathogens and triggering the immune response.…”

Toll-Like Receptor Polymorphisms, Inflammatory and Infectious Diseases, Allergies, and Cancer

“…For instance, the c.32A > T variation in TLR7 was over-represented in female patients with chronic HCV infection compared to patients with other chronic liver diseases and healthy controls, and its presence had a predictive value of an unfavorable outcome of IFN-a therapy, suggesting that variations of TLR7 alter the immune response to HCV infection (Schott 2008). Likewise, polymorphisms in TLR7 and TLR8 have been linked to susceptibility to HCV infection in the Taiwanese population (Wang and others 2011).…”