Toll receptor polymorphisms and carotid artery intima-media thickness.
OBJECTIVE
Inflammation is a key mechanism in atherosclerosis. Variation in genes encoding inflammatory responses may therefore influence atherosclerosis risk possibly through interaction with chronic infections and proinflammatory environmental risk factors such as smoking, diabetes, and obesity. The Toll-like receptor family (TLRs) genes TLR2 and TLR4, both involved in the inflammatory process, are potential candidates and TLR-4 has been previously associated with cardiovascular disease, although other studies have failed to confirm this.


METHODS
A total of 3000 individuals from the prospective community-based Carotid Atherosclerosis Progression Study (CAPS) were genotyped for single nucleotide polymorphisms: TLR2 (Arg753Gln, -16934 A/T) and TLR4 (D299G, T399I). Associations were determined with common carotid artery intima-media thickness (IMT) at baseline and also progression of IMT over the 3-year follow-up period. Gene-environment interactions with high sensitive C-reactive protein, smoking, body mass index, and diabetes were determined.


RESULTS
There was no association between single nucleotide polymorphisms or haplotypes in either TLR4 or TLR2 and either baseline IMT or progression of IMT over the 3-year follow up. There were no interactions among the three proinflammatory risk factors. No genotype or haplotype was associated with high sensitive C-reactive protein.


CONCLUSIONS
In this large community population, we found no evidence for genetic variation in these two TLRs being risk factors for increased IMT either directly or through interaction with proinflammatory risk factors. We were unable to confirm associations with the TLR4 polymorphisms reported in previous smaller studies.
Labrum
Robyn
R
Centre for Clinical Neuroscience, St. George's University of London, London, UK.
Bevan
Steve
S
Sitzer
Matthias
M
Lorenz
Matthias
M
Markus
Hugh S
HS
D000328:Adult; D002097:C-Reactive Protein / Q000378:metabolism; D002339:Carotid Arteries / Q000473:pathology* / Q000503:physiopathology; D002340:Carotid Artery Diseases / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D015331:Cohort Studies; D048909:Diabetes Complications / Q000453:epidemiology; D004781:Environmental Exposure; D005260:Female; D005819:Genetic Markers / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005820:Genetic Testing; D006801:Humans; D007249:Inflammation / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D009765:Obesity / Q000453:epidemiology; D011110:Polymorphism, Genetic / Q000235:genetics*; D011446:Prospective Studies; D012907:Smoking / Q000453:epidemiology; D051195:Toll-Like Receptor 2 / Q000235:genetics; D051197:Toll-Like Receptor 4 / Q000235:genetics; D051193:Toll-Like Receptors / Q000235:genetics*; D017539:Tunica Intima / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D017540:Tunica Media / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D006113:United Kingdom / Q000453:epidemiology
D005819:Genetic Markers; C495342:TLR2 protein, human; C495345:TLR4 protein, human; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D002097:C-Reactive Protein