The human toll-like receptor (TLR) family consists of 10 receptors that are critically important within innate immunity. TLRs recognise and respond to diverse microbial molecules, enable the innate immune system to discriminate between groups of pathogens, and enable the induction of appropriate effector cascade responses. Hepatitis C virus (HCV) has various effects upon TLR pathway stimulation in many cellular compartments and in this way it is able to both stimulate pro-inflammatory cytokine production, leading to liver damage, and evade immune responses to establish viral persistence.
AIMS AND METHODS
The aim of this work was to investigate the association of TLR single nucleotide polymorphisms (SNPs) with the outcome of HCV infection. Four SNPS of TLR2 and TLR4 were genotyped using real time PCR (TaqMan allelic discrimination kit [Applied Biosystems]) according to the manufacturer’s protocol. A total of 392 families (1,176 individuals) were recruited for this study from both the upper and lower regions of Egypt (East and West Nile Delta); we compared the risk of allele carriers of selected markers within different groups. These groups included spontaneous virus clearance (SVC) (n=108), chronic HCV patients (n=549), and negative control individuals (n=519). Bothrs121917864 (C/T) and rs5743708 (G/A) were genotyped for TLR2, while rs4986791 (C/T) and rs62522600 (G/A) were genotyped for TLR4.
Regarding TLR2, the T allele of rs121917864 (C/T) was found to be significantly higher in the HCV group compared with both the control and SVC groups (odds ratio [OR]: 2.960 [95% confidence interval (CI): 1.95–3.45, p=0.0005] and 2.635 [95% CI: 2.14–4.15, p=0.0001], respectively). The A allele of rs5743708 (G/A) was significantly associated with the HCV group compared to the control and SVC groups (OR: 2.2071, [95% CI: 1.2056–4.0404, p=0.007] and 2.1321 [95% CI: 1.5528–2.9274, p=0.0001], respectively). On the other hand, TLR4 genotyping revealed that carriers of the C allele of rs4986791 were significantly higher in both the negative and spontaneous groups, compared to that of the chronic HCV group (OR: 0.4843 [95% CI: 0.388–0.646] and 0.4449 [95% CI: 0.2917–0.6787], respectively), simultaneously indicating that the C allele acts as a protective allele against HCV infection and the development of chronic HCV. Linkage disequilibrium of rs4986791 and rs62522600 SNPs indicated that carriers of the TA haplotype were significantly higher within the chronic HCV group compared to the negative group (OR: 3.8 [95% CI: 2.95–4.95]). No individual from the spontaneous group was found to be a carrier for the TA haplotype, revealing the role of the TA haplotype as a risk indicator for HCV infection. On the other hand, carriers of the haplotype GC were significantly higher within the SVC and negative groups, compared to the chronic HCV group (OR: 0.2010 [95% CI: 0.1299–0.3109, p=0.0001] and OR: 0.2595 [95% CI: 0.0769–0.8762, p=0.02], respectively).
This study demonstrated that spontaneous clearance of HCV was associated with the C allele of rs4986791 of the TLR4 allele and the GC haplotype of TLR4. The chronicity of HCV infection was associated with the risk haplotype (TA) of the TLR4 allele, as well as the T allele of rs121917864 and the A allele of rs5743708 of TLR2.
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