The association between toll-like receptor 7 single nucleotide polymorphisms and severity of hand, foot and mouth disease caused by enterovirus 71 infection

Abstract

Objective To explore the association between toll-like receptor 7 (TLR7) single nucleotide polymorphisms (SNP) and susceptibility of hand, foot and mouth disease caused by enterovirus (EV)71 infection. Methods The genotype of SNP (rs179019 and rs3853839) was determined in 775 EV7l-infected cases (including 439 mild cases and 336 severe cases) and 748 healthy control cases with TaqMan assay. The difference of allele frequencies was compared. The difference of TLR7 mRNA expression in peripheral blood mononuclear cells (PBMCs) derived from different SNP genotype carriers was detected. PBMCs derived from different SNP genotype carriers were stimulated by imiquimod and the TLR7-specific interferon-α(IFN-α) and interleukin-6 (IL-6) secretions were detected. Logistic regression was used to analyze for genotype frequency. Results The frequencies of rs3853839 genotype CC and CG in female patients of severe group were significantly higher than mild group (rs3853839 GC: OR=0.36, 95%CI: 0.14-0.82, P=0.01; rs3853839 CC: OR=0.19, 95%CI: 0.11-0.69, P=0.01). In addition, the frequency of rs3853839 genotype C in severe male group was significantly higher compared with that in mild group (OR=0.35, 95%CI: 0.19-0.63, P=0.01). Female carriers with rs3853839 genotype CC had significantly lower TLR7 mRNA expression than genotype GC and GG (CC vs GG: P=0.005; CC vs GC: P=0.016). Male carriers with rs3853839 genotype C also had significantly lower TLR7 mRNA expression than genotype G (C vs G: P=0.004). After stimulation of imiquimod, the expression of IFN-α (CC vs GG, P=0.001; CC vs GC: P=0.026) and IL-6 productions (CC vs GG: P=0.001; CC vs GC: P=0.011) were significantly lower in female carriers with rs3853839 genotype CC. The same patterns were observed in male carriers with rs3853839 genotype CC (IFN-α: P=0.003; IL-6: P=0.018). Conclusions The rs3853839C allele is the risk factor of severe infection of EV71, which may be due to specific cytokine profiles in rs3853839C allele carriers in children. Key words: Toll-like receptor 7; Polymorphism, single nucleotide; Human enterovirus 71