Functional polymorphisms of Toll-like receptors 2 and 4 alter the risk for colorectal carcinoma in Europeans

BackgroundColon carcinogenesis is associated with increased expression levels of Toll-like receptor 2 and Toll-like receptor 4.AimTo determine in a Caucasian population the role of Toll-like receptor 2 and Toll-like receptor 4 polymorphisms in colorectal cancer development.MethodsHospital based multicentre case control study involving 193 colorectal cancer patients and 278 healthy individuals. DNA samples were extracted from blood cells and genotyping of TLR2+597T>C, TLR2−4760T>C, TLR4−3745A>G, TLR2Arg753Gln, TLR4Asp299Gly was performed. Functionality of risk polymorphisms was evaluated through production of TNF-α in cell culture and Toll-like receptors levels quantified by real-time RT-PCR.ResultsTLR2+597CC homozygous had 5-fold decreased risk (odds ratio (OR) = 0.21, 95% CI: 0.09–0.50, p < 0.001) and TLR4 299Gly homozygous 3-fold increased risk of colorectal cancer (OR = 3.30, 95% CI: 1.18–9.28, p = 0.015). In stratified analysis, TLR2+597CC genotype protective effect was even higher in overweight individuals (OR = 0.17, 95% CI: 0.06–0.53, p < 0.001) and in never smokers (OR = 0.11, 95% CI: 0.02–0.51, p = 0.001). Also, the increased risk effect for TLR4 299Gly homozygous genotype was higher in overweight individuals (OR = 8.67, 95% CI: 1.11–87.85, p = 0.011). TLR2+597T>C polymorphism conferred 41% less (p = 0.03) and TLR4Asp299Gly 65% more TNF-α production (p = 0.02) with no differences in Toll-like receptors levels.ConclusionFunctional Toll-like receptor 2 and Toll-like receptor 4 polymorphisms significantly alter the risk to have colorectal cancer. Obesity and smoking may influence the risk for colorectal cancer in individuals presenting these genetic profiles.