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. METHODS AND 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.
RCT Entities:
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. METHODS AND 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.
Authors: Daniel R Anderson; Michael J Duryee; Rajeev K Anchan; Robert P Garvin; Michael D Johnston; Thomas R Porter; Geoffrey M Thiele; Lynell W Klassen Journal: J Biol Chem Date: 2010-10-21 Impact factor: 5.157
Authors: Alexander Riad; Henriette Meyer zu Schwabedissen; Kerstin Weitmann; Lars R Herda; Marcus Dörr; Klaus Empen; Arne Kieback; Astrid Hummel; Marcus Reinthaler; Marcus Grube; Karin Klingel; Matthias Nauck; Reinhard Kandolf; Wolfgang Hoffmann; Heyo K Kroemer; Stephan B Felix Journal: J Biol Chem Date: 2012-05-29 Impact factor: 5.157
Authors: Peter Reismann; Christoph Lichy; Gottfried Rudofsky; Per M Humpert; Just Genius; Tuan-Dong Si; Christof Dörfer; Armin J Grau; Andreas Hamann; Werner Hacke; Peter P Nawroth; Angelika Bierhaus Journal: J Neurol Date: 2004-07 Impact factor: 4.849
Authors: Kathrin S Michelsen; Michelle H Wong; Prediman K Shah; Wenxuan Zhang; Juliana Yano; Terence M Doherty; Shizuo Akira; Tripathi B Rajavashisth; Moshe Arditi Journal: Proc Natl Acad Sci U S A Date: 2004-07-12 Impact factor: 11.205
Authors: Yeun Sun Kim; You Jin Hwang; Sung Yong Kim; Sun Mee Yang; Ki Young Lee; Ie Byung Park Journal: Yonsei Med J Date: 2008-02-29 Impact factor: 2.759