The toll‐like receptor 2 (TLR2) ‐196 to ‐174 del/ins polymorphism affects viral loads and susceptibility to hepatocellular carcinoma in chronic hepatitis C

Abstract

Chronic hepatitis C virus (HCV) infection is a major risk factor for hepatocellular carcinoma (HCC). HCV proteins core and NS3 can bind to toll-like receptor 2 (TLR2) and trigger inflammatory responses. Polymorphisms in the TLR2 gene predispose to various forms of malignancy but have not been studied in HCV-associated HCC. Here, we investigated whether single nucleotide polymorphisms (SNPs), rs4696480, rs5743708, rs5743704 and the -196 to -174 del/ins polymorphism of the TLR2 gene affect the risk for HCC in chronic hepatitis C. The study involved 189 and 192 HCV genotype 1 infected patients with and without HCC, respectively, as well as 347 healthy controls. TLR2 alleles were determined by hybridization probe assays and allele-specific short fragment polymerase chain reaction on a LightCycler system. All TLR2 polymorphisms matched the HardyWeinberg equilibrium in each study group. Although TLR2 SNPs showed no effect, the frequency of the TLR2 -196 to -174 del allele was significantly higher in patients with HCV-associated HCC (22.5%) than in HCV-infected patients without HCC (15.6%, p 5 0.016) and healthy controls (15.3%, p 5 0.003). HCV-infected carriers of a TLR2 -196 to -174 del allele had significantly higher HCV viral loads than TLR2 -196 to -174 ins/ins homozygous patients (p 5 0.031). Finally, in carriers of the TLR2 -196 to -174 del allele, stimulation of monocytes resulted in significantly lower TLR2 expression levels and interleukin-8 (IL-8) induction than in individuals with the TLR2 -196 to -174 ins/ins genotype (p < 0.05). Our data suggest the TLR2 -196 to -174 del allele to affect HCV viral loads and to increase the risk for HCC in HCV genotype1-infected patients.

Association between Toll-Like Receptor 4 (Thr399Ile and Asp299Gly), Toll-Like Receptor 2 196-174 Deletion Polymorphisms with cryptosporidiosis

“…In a study on neurocysticircosis (NCC), TLR4 Asp299Gly and Thr399Ile polymorphisms were associated with its occurrence (P < 0.001 for Asp299Gly; P = 0.003 for Thr399Ile) and progression to symptomatic NCC, compared with control subjects or asymptomatic NCC [20]. In another study, the frequency of the TLR2 196 -174 del allele was higher in patients with HCV-associated hepatocellular carcinoma (22.5%) than in HCV-infected patients without hepatocellular carcinoma (15.6%, P = 0.016) and healthy controls (15.3%, P = 0.003) [21]. Thus, association between genetic polymorphisms of innate immunity components and outcome might depend on the type of infection or pathogen involved.…”

Lack of Association of Three Common Polymorphisms in Toll-like receptors (TLRs), TLR2+597T>C, +1350C>T and Arg753Gln with Cancer Risk: a Meta-analysis

“…As shown in Figure 1, a total of 14 studies were finally identified (Nieters et al, 2006;Etokebe et al, 2009;Purdue et al, 2009;Ashton et al, 2010;Balistreri et al, 2010;Gast et al, 2011;Zeng et al, 2011;Junjie et al, 2012;Kim et al, 2012;Nischalke et al, 2012;Slattery et al, 2012;Yang et al, 2012;Pimentel-Nunes et al, 2013). For the +597T>C polymorphism (rs3804099), 8 studies were available, including a total of 3987 cases and 5079 controls.…”

Polymorphisms of glutathione S-transferase π 1 and toll-like receptors 2 and 9: Association with breast cancer susceptibility

“…This substitution may significantly alter the function of the promoter, likely leading to decreased transcription of TLR2 (14). This polymorphism is reported to be associated with increased susceptibility to hepatocellular carcinoma and gastric cancer (15,16).…”