Toll-like receptor 4 Asp299Gly gene polymorphism and risk of atherothrombosis

Background and Purpose - Recent findings of an association between a functional toll-like receptor 4 (TLR4) D299G gene variant and reduced risk of atherothrombotic disorders have generated great interest. Methods - We evaluated the TLR4 D299G polymorphism among 695 individuals with incident myocardial infarction (MI) or stroke and among 695 age- and smoking-matched individuals who remained free of reported cardiovascular disease during follow-up within the Physicians' Health Study. Results - Overall, we observed little evidence of association between the D299G polymorphism and risk of any atherothrombotic event ( P = 0.25), incident MI ( P = 0.89), or stroke ( P = 0.09), assuming an additive model. Adjusting for traditional cardiovascular risk factors or assuming a dominant model yielded similar null findings. Whereas the observed carrier frequency of the D299G polymorphism in our data (13.0%) is consistent with those observed in most other studies, it was higher than the 6.8% carrier frequency observed in the initial study that suggested a protective effect for this gene variant. Thus, this former association may have been caused, in part, by an underestimation of the control frequency. Conclusion - In contrast to previous data, the D299G TLR4 polymorphism was not associated with risk of incident MI or stroke in this large prospective study of US men.