Published online before print April 27, 2006, doi: 10.1161/01.ATV.0000223867.25324.1a
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© 2006 American Heart Association, Inc.
Thrombosis |
Contribution of Gene Sequence Variations of the Hepatic Cytochrome P450 3A4 Enzyme to Variability in Individual Responsiveness to Clopidogrel
From the Division of Cardiology (D.J.A., M.A.C., T.A.B.), University of Florida, Shands Jacksonville; Cardiovascular Institute (A.F.-O., E.B., C.R., M.S., R.H., R.M., J.E., F.A., C.B., C.M.), San Carlos University Hospital, Madrid, Spain; and the Department of Mother and Child & Biology-Genetics (U.C., E.T., P.F.), University of Verona, Italy.
Correspondence to Dominick J Angiolillo, MD, PhD, FACC, FESC, Division of Cardiology, University of Florida, Shands Jacksonville, 655 West 8th St, Jacksonville, FL 32209. E-mail dominick.angiolillo{at}jax.ufl.edu
Objectives— Metabolic activity of cytochrome P450 (CYP) 3A4 has been associated with clopidogrel response variability. Because metabolic activity of CYP3A4 is genetically regulated, we hypothesized that genetic variations of this enzyme may contribute to clopidogrel response variability.
Methods and Results— The CYP3A4*1B, CYP3A4*3, IVS7+258A>G, IVS7+894C>T, and IVS10+12G>A polymorphisms of the CYP3A4 gene were assessed in 82 patients in a steady phase of clopidogrel therapy. Glycoprotein (platelet glycoprotein (GP) IIb/IIIa receptor activation and platelet aggregation were assessed. A cohort of 45 clopidogrel-naïve patients was studied to determine the modulating effects of these polymorphisms after loading dose (300 mg) administration. Only the IVS7+258A>G, IVS7+894C>T, and IVS10+12G>A polymorphisms were sufficiently polymorphic. During the steady phase of clopidogrel treatment, IVS10+12A allele carriers had reduced GP IIb/IIIa activation (P=0.025) and better responsiveness (P=0.02); similarly, clopidogrel-naïve patients carriers of the IVS10+12A allele had reduced GP IIb/IIIa activation during the first 24 hours after a loading dose (P=0.025), increased platelet inhibition (P=0.006), and a more optimal drug response (P=0.003). This polymorphism did not influence platelet aggregation profiles. No association was observed between the other polymorphisms and clopidogrel responsiveness.
Conclusions— The IVS10+12G>A polymorphism of the CYP3A4 gene modulates platelet activation in patients treated with clopidogrel and may therefore contribute to clopidogrel response variability.
Gene sequence variations of CYP3A4 have been suggested to contribute to clopidogrel responsiveness. Carriers of the IVS10+12A allele had reduced GP IIb/IIIa activation (P=0.025) in the steady phase of treatment and more optimal responsiveness (P=0.003) after loading dose administration. In conclusion, genetic variations of CYP3A4 may contribute clopidogrel response variability.
Key Words: clopidogrel • platelet • polymorphism
Related Article:
Arterioscler Thromb Vasc Biol 2006 26: 1681-1683.
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