CYP2C19*2 and CYP2C9*3 alleles are associated with stent thrombosis: a case-control study.
OBJECTIVE
despite treatment with clopidogrel on top of aspirin, stent thrombosis (ST) still occurs being the most serious complication after percutaneous coronary interventions (PCIs). In this study, we aimed to determine the effect of variations in genes involved in the absorption (ABCB1 C1236T, G2677T/A, C3435T), metabolism (CYP2C19*2 and *3, CYP2C9*2 and *3, CYP3A4*1B and CYP3A5*3), and pharmacodynamics (P2Y1 A1622G) of clopidogrel on the occurrence of ST.


RESULTS
the selected genetic variants were assessed in 176 subjects who developed ST while on dual antiplatelet therapy with aspirin and clopidogrel and in 420 control subjects who did not develop adverse cardiovascular events, including ST, within 1 year after stenting. The timing of the definite ST was acute in 66, subacute in 87, and late in 23 cases. The presence of the CYP2C19*2 and CYP2C9*3 variant alleles was significantly associated with ST (OR(adj): 1.7, 95% CI: 1.0-2.6, P = 0.018 and OR(adj): 2.4, 95% CI: 1.0-5.5, P = 0.043, respectively). The influence of CYP2C19*2 (OR(adj): 2.5, 95% CI: 1.1-5.5, P = 0.026) and CYP2C9*3 (OR(adj): 3.3, 95% CI: 1.1-9.9, P = 0.031) was most strongly associated with subacute ST. No significant associations of the other genetic variations and the occurrence of ST were found.


CONCLUSIONS
carriage of the loss-of-function alleles CYP2C19*2 and CYP2C9*3 increases the risk on ST after PCI.
Harmsze
Ankie M
AM
Department of Clinical Pharmacy, St Antonius Hospital, PO Box 2500, Nieuwegein 3430 EM, The Netherlands. a.harmsze@antoniusziekenhuis.nl
van Werkum
Jochem W
JW
Ten Berg
Jurriën M
JM
Zwart
Bastiaan
B
Bouman
Heleen J
HJ
Breet
Nicoline J
NJ
van 't Hof
Arnoud W J
AW
Ruven
Hendrik J T
HJ
Hackeng
Christian M
CM
Klungel
Olaf H
OH
de Boer
Anthonius
A
Deneer
Vera H M
VH
D000368:Aged; D015906:Angioplasty, Balloon, Coronary / Q000379:methods; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D001241:Aspirin / Q000627:therapeutic use*; D001807:Blood Vessel Prosthesis; D016022:Case-Control Studies; D000077144:Clopidogrel; D065731:Cytochrome P-450 CYP2C19; D065729:Cytochrome P-450 CYP2C9; D004359:Drug Therapy, Combination; D005260:Female; D005838:Genotype; D006083:Graft Occlusion, Vascular / Q000235:genetics*; D006579:Heterozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D010975:Platelet Aggregation Inhibitors / Q000627:therapeutic use*; D015607:Stents; D013988:Ticlopidine / Q000031:analogs & derivatives* / Q000627:therapeutic use
D010975:Platelet Aggregation Inhibitors; D000077144:Clopidogrel; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D013988:Ticlopidine; D001241:Aspirin