Copyright © 2004 by the European Society of Cardiology.
Clinical research
Association of hypo-responsive toll-like receptor 4 variants with risk of myocardial infarction
a Experimental Cardiovascular Research Unit, Center for Molecular Medicine, Karolinska Institute, Stockholm, Sweden
b Division of Cardiovascular Epidemiology, Institute for Environmental Medicine, Karolinska Institute, Stockholm, Sweden
c Atherosclerosis Research Unit, King Gustaf V Research Institute, Karolinska Institute, Stockholm, Sweden
d Center of Metabolism and Endocrinology, Center of Infectious Medicine, Karolinska University Hospital, Huddinge, Sweden
e Division of Clinical Chemistry and Blood Coagulation, Department of Surgical Sciences, Karolinska Institute, Stockholm, Sweden
f Department of Cardiology, Karolinska University Hospital, Stockholm, Sweden
Received January 28, 2004;
revised April 20, 2004;
accepted May 5, 2004
* Corresponding author. Tel.: +46-8-517 73207; fax: +46-8-31 3147
zhong-qun.yan{at}cmm.ki.se
See page 1378 for the editorial comment on this article1
Aim 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).
Methods and results 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%, 
). 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.
Conclusion 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.
Key Words: Toll-like receptor 4 • Myocardial infarction • Immune system • Single nucleotide polymorphism • Genetics
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