Variants of Toll-Like Receptor 4 Modify the Efficacy of Statin Therapy and the Risk of Cardiovascular Events

TLDR

Atherosclerosis is increasingly viewed as a chronic inflammatory disease. The study aimed to determine whether TLR4 polymorphisms Asp299Gly and Thr399Ile are associated with coronary atherosclerosis and predict cardiovascular event risk, and whether they influence pravastatin efficacy. 655 men with angiographically documented coronary disease were genotyped and randomized to pravastatin or placebo for 2 years in a prospective cholesterol‑lowering trial. Although genotype did not affect baseline risk factors, lipid changes, or atherosclerosis progression, Asp299Gly carriers on pravastatin had a dramatically lower event rate (2.0 % vs 29.6 % untreated) and derived greater benefit than noncarriers (risk reduced from 18.1 % to 11.5 %), showing the variant predicts both event risk and pravastatin efficacy.

Abstract

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.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).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.