title: 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 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.
authors.affiliation: Department of Internal Medicine I, University of Bonn, Bonn, Germany. nischalke@ukb.uni-bonn.de
authors.forename: Hans-Dieter
authors.initials: HD
authors.lastname: Nischalke
authors.forename: Martin
authors.initials: M
authors.lastname: Coenen
authors.forename: Cordula
authors.initials: C
authors.lastname: Berger
authors.forename: Katharina
authors.initials: K
authors.lastname: Aldenhoff
authors.forename: Tobias
authors.initials: T
authors.lastname: Müller
authors.forename: Thomas
authors.initials: T
authors.lastname: Berg
authors.forename: Benjamin
authors.initials: B
authors.lastname: Krämer
authors.forename: Christian
authors.initials: C
authors.lastname: Körner
authors.forename: Margarete
authors.initials: M
authors.lastname: Odenthal
authors.forename: Falko
authors.initials: F
authors.lastname: Schulze
authors.forename: Frank
authors.initials: F
authors.lastname: Grünhage
authors.forename: Jacob
authors.initials: J
authors.lastname: Nattermann
authors.forename: Tilman
authors.initials: T
authors.lastname: Sauerbruch
authors.forename: Ulrich
authors.initials: U
authors.lastname: Spengler
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000378:metabolism / Q000821:virology*; D016022:Case-Control Studies; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D016174:Hepacivirus / Q000235:genetics; D019698:Hepatitis C, Chronic / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D016209:Interleukin-8 / Q000235:genetics / Q000378:metabolism; D008113:Liver Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000821:virology*; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D051195:Toll-Like Receptor 2 / Q000235:genetics*; D019562:Viral Load; D055815:Young Adult
chemical_list: D016209:Interleukin-8; C495342:TLR2 protein, human; D051195:Toll-Like Receptor 2