Association of hypo-responsive toll-like receptor 4 variants with risk of myocardial infarction.

Abstract

Toll-like receptor 4 (TLR4) is a receptor for bacterial lipopolysaccharide (LPS) and heat shock protein essential for innate immunity. Recent studies imply that TLR4 polymorphisms might affect atherogenesis. In this study we investigated the impact of LPS-hypo-responsive TLR4 variants on the risk of myocardial infarction (MI). Using TaqMan PCR technology, we determined the prevalence of the Asp299Gly and Thr399Ile polymorphisms in the TLR4 gene, and their association with MI in a study of 1213 survivors of a first MI and 1561 controls from the Stockholm region. The frequency was 0.096 for carriers of both 299Gly and 399Ile, and 0.006 for carriers of 399Ile alone. Carriers of both 299Gly and 399Ile were more frequent among the male cases than the male controls (10.7% vs 7.9%, p = 0.004). Compared with wild-type carriers, men with the 299Gly and the 399Ile TLR4 genotype had an increased risk of MI (OR [95% CI]: 1.4 [1.0;1.9]) whereas no association was observed for women. Furthermore a synergistic interaction was found between the TLR4 polymorphism and smoking in men. The association found between TLR4 genotype and risk of MI suggests that TLR4 genetic variants could potentially affect the susceptibility to MI and that TLR4-mediated innate immunity is implicated in the pathogenesis of MI.