title: Functional polymorphisms of Toll-like receptors 2 and 4 alter the risk for colorectal carcinoma in Europeans.
abstract: BACKGROUND
  Colon carcinogenesis is associated with increased expression levels of Toll-like receptor 2 and Toll-like receptor 4.
  
  
  OBJECTIVE
  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-α 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-α production (p=0.02) with no differences in Toll-like receptors levels.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Physiology and Cardiothoracic Surgery, Cardiovascular Research & Development Unit, Faculty of Medicine, University of Porto, Portugal. pedronunesml@gmail.com
authors.forename: Pedro
authors.initials: P
authors.lastname: Pimentel-Nunes
authors.forename: Ana Luísa
authors.initials: AL
authors.lastname: Teixeira
authors.forename: Carina
authors.initials: C
authors.lastname: Pereira
authors.forename: Mónica
authors.initials: M
authors.lastname: Gomes
authors.forename: Catarina
authors.initials: C
authors.lastname: Brandão
authors.forename: Catarina
authors.initials: C
authors.lastname: Rodrigues
authors.forename: Nádia
authors.initials: N
authors.lastname: Gonçalves
authors.forename: Inês
authors.initials: I
authors.lastname: Boal-Carvalho
authors.forename: Roberto
authors.initials: R
authors.lastname: Roncon-Albuquerque
authors.forename: Luís
authors.initials: L
authors.lastname: Moreira-Dias
authors.forename: Adelino F
authors.initials: AF
authors.lastname: Leite-Moreira
authors.forename: Rui
authors.initials: R
authors.lastname: Medeiros
authors.forename: Mário
authors.initials: M
authors.lastname: Dinis-Ribeiro
mesh_terms: D000368:Aged; D016022:Case-Control Studies; D015179:Colorectal Neoplasms / Q000175:diagnosis / Q000235:genetics*; D017931:DNA Primers / Q000737:chemistry; D005260:Female; D005786:Gene Expression Regulation; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D009765:Obesity; D020641:Polymorphism, Single Nucleotide / Q000235:genetics / Q000502:physiology; D012333:RNA, Messenger / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D018570:Risk Assessment; D012907:Smoking; D051195:Toll-Like Receptor 2 / Q000235:genetics* / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000235:genetics* / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D044465:White People / Q000235:genetics*
chemical_list: D017931:DNA Primers; D012333:RNA, Messenger; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha