title: Contribution of gene sequence variations of the hepatic cytochrome P450 3A4 enzyme to variability in individual responsiveness to clopidogrel.
abstract: OBJECTIVE
  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.
  
  
  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.
authors.affiliation: Division of Cardiology, University of Florida, Shands Jacksonville, 655 West 8th St, Jacksonville, FL 32209, USA. dominick.angiolillo@jax.ufl.edu
authors.forename: Dominick J
authors.initials: DJ
authors.lastname: Angiolillo
authors.forename: Antonio
authors.initials: A
authors.lastname: Fernandez-Ortiz
authors.forename: Esther
authors.initials: E
authors.lastname: Bernardo
authors.forename: Celia
authors.initials: C
authors.lastname: Ramírez
authors.forename: Ugo
authors.initials: U
authors.lastname: Cavallari
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Trabetti
authors.forename: Manel
authors.initials: M
authors.lastname: Sabaté
authors.forename: Rosana
authors.initials: R
authors.lastname: Hernández
authors.forename: Raul
authors.initials: R
authors.lastname: Moreno
authors.forename: Javier
authors.initials: J
authors.lastname: Escaned
authors.forename: Fernando
authors.initials: F
authors.lastname: Alfonso
authors.forename: Camino
authors.initials: C
authors.lastname: Bañuelos
authors.forename: Marco A
authors.initials: MA
authors.lastname: Costa
authors.forename: Theodore A
authors.initials: TA
authors.lastname: Bass
authors.forename: Pier Franco
authors.initials: PF
authors.lastname: Pignatti
authors.forename: Carlos
authors.initials: C
authors.lastname: Macaya
mesh_terms: D000225:Adenine; D000483:Alleles; D000925:Anticoagulants / Q000627:therapeutic use; D001241:Aspirin / Q000627:therapeutic use; D001792:Blood Platelets / Q000187:drug effects; D000077144:Clopidogrel; D015331:Cohort Studies; D003324:Coronary Artery Disease / Q000097:blood / Q000188:drug therapy* / Q000235:genetics*; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D014644:Genetic Variation; D005838:Genotype; D006147:Guanine; D006801:Humans; D007438:Introns; D008099:Liver / Q000201:enzymology*; D010974:Platelet Aggregation; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use*; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000378:metabolism; D011110:Polymorphism, Genetic; D013988:Ticlopidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use
chemical_list: D000925:Anticoagulants; D010975:Platelet Aggregation Inhibitors; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D006147:Guanine; D003577:Cytochrome P-450 Enzyme System; D000077144:Clopidogrel; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D000225:Adenine; D013988:Ticlopidine; D001241:Aspirin