The Toll-Like Receptor 2 (TLR2) -196 to -174 del/ins Polymorphism Affects Viral Loads and Susceptibility to Hepatocellular Carcinoma in Chronic Hepatitis C

Int J Cancer. 2012 Mar 15;130(6):1470-5. doi: 10.1002/ijc.26143. Epub 2011 Jun 18.

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 Hardy-Weinberg 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 = 0.016) and healthy controls (15.3%, p = 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 = 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Alleles
  • Carcinoma, Hepatocellular / genetics*
  • Carcinoma, Hepatocellular / metabolism
  • Carcinoma, Hepatocellular / virology*
  • Case-Control Studies
  • Female
  • Genetic Predisposition to Disease
  • Genotype
  • Hepacivirus / genetics
  • Hepatitis C, Chronic / genetics*
  • Hepatitis C, Chronic / metabolism
  • Humans
  • Interleukin-8 / genetics
  • Interleukin-8 / metabolism
  • Liver Neoplasms / genetics*
  • Liver Neoplasms / metabolism
  • Liver Neoplasms / virology*
  • Male
  • Middle Aged
  • Polymorphism, Genetic
  • Toll-Like Receptor 2 / genetics*
  • Viral Load
  • Young Adult

Substances

  • Interleukin-8
  • TLR2 protein, human
  • Toll-Like Receptor 2