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

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... little evidence of association between the D299G polymorphism and risk of any atherothrombotic event (Pϭ0.25), incident MI (Pϭ0.89), or stroke (Pϭ0.09), 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. (Stroke. 2005;36:154-157.)