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


CONCLUSIONS
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.
Zee
Robert Y L
RY
Center for Cardiovascular Disease Prevention, and the Division of Preventive Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Mass 02215, USA. rzee@rics.bwh.harvard.edu
Hegener
Hillary H
HH
Gould
Jessica
J
Ridker
Paul M
PM
D019943:Amino Acid Substitution; D001224:Aspartic Acid / Q000235:genetics; D016022:Case-Control Studies; D020022:Genetic Predisposition to Disease; D005998:Glycine / Q000235:genetics; D006801:Humans; D015994:Incidence; D008562:Membrane Glycoproteins / Q000235:genetics*; D008875:Middle Aged; D009203:Myocardial Infarction / Q000453:epidemiology / Q000235:genetics*; D011110:Polymorphism, Genetic; D011446:Prospective Studies; D011956:Receptors, Cell Surface / Q000235:genetics*; D020521:Stroke / Q000453:epidemiology / Q000235:genetics*; D013927:Thrombosis / Q000453:epidemiology / Q000235:genetics*; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors
D008562:Membrane Glycoproteins; D011956:Receptors, Cell Surface; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D001224:Aspartic Acid; D005998:Glycine