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

Background: Colon carcinogenesis is associated with increased expression levels of Toll-like receptor 2 and Toll-like receptor 4. Aim: To determine in a Caucasian population the role of Toll-like receptor 2 and Toll-like receptor 4 polymorphisms in colorectal cancer development. Methods: Hospital 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-alpha in cell culture and Toll-like receptors levels quantified by real-time RT-PCR. Results: TLR2+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-a production (p = 0.02) with no differences in Toll-like receptors levels. Conclusion: Functional 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. (C) 2012 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.