Variants of toll-like receptor 4 modify the efficacy of statin therapy and the risk of cardiovascular events.
BACKGROUND
Atherosclerosis is increasingly considered to be a chronic inflammatory process. We examined whether genetic variants of the toll-like receptor 4 (TLR4), which are correlated with impaired innate immunity and with progression of carotid atherosclerosis, are also associated with coronary atherosclerosis and predict the risk of cardiovascular events.


RESULTS
Two polymorphisms of the TLR4 gene (Asp299Gly and Thr399Ile) were determined in 655 men with angiographically documented coronary atherosclerosis. All patients participated in a prospective cholesterol-lowering trial evaluating the effect on coronary artery disease and were randomly assigned to either pravastatin or placebo for 2 years. There were no significant differences between genetically defined subgroups with respect to baseline risk factors, treatment, or in-trial changes of lipid, lipoprotein, or angiographic measurements. Genotype was not associated with progression of atherosclerosis. In the pravastatin group, 299Gly carriers had a lower risk of cardiovascular events during follow-up than noncarriers (2.0% versus 11.5%, P=0.045). Among noncarriers, pravastatin reduced the risk of cardiovascular events from 18.1% to 11.5% (P=0.03), whereas among 299Gly carriers this risk was strikingly reduced from 29.6% to 2.0% (P=0.0002, P=0.025 for interaction).


CONCLUSIONS
Among symptomatic men with documented coronary artery disease, the TLR4 Asp299Gly polymorphism was associated with the risk of cardiovascular events. This variant also modified the efficacy of pravastatin in preventing cardiovascular events, such that carriers of the variant allele had significantly more benefit from pravastatin treatment.
Boekholdt
S Matthijs
SM
Leiden University Medical Center, Department of Cardiology C5-P, Albinusdreef 2, PO Box 9600, 2300 RC Leiden, The Netherlands. j.w.jukema@lumc.nl
Agema
Willem R P
WR
Peters
Ron J G
RJ
Zwinderman
Aeilko H
AH
van der Wall
Ernst E
EE
Reitsma
Pieter H
PH
Kastelein
John J P
JJ
Jukema
J Wouter
JW
D019943:Amino Acid Substitution; D015331:Cohort Studies; D003324:Coronary Artery Disease / Q000188:drug therapy* / Q000235:genetics*; D018450:Disease Progression; D018572:Disease-Free Survival; D029721:Drosophila Proteins; D005787:Gene Frequency; D006580:Genetic Carrier Screening; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use*; D015994:Incidence; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics*; D015337:Multicenter Studies as Topic / Q000706:statistics & numerical data; D011110:Polymorphism, Genetic; D017035:Pravastatin / Q000627:therapeutic use; D011446:Prospective Studies; D016032:Randomized Controlled Trials as Topic / Q000706:statistics & numerical data; D011956:Receptors, Cell Surface / Q000235:genetics*; D018570:Risk Assessment; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D016896:Treatment Outcome
D029721:Drosophila Proteins; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008562:Membrane Glycoproteins; D011956:Receptors, Cell Surface; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D017035:Pravastatin