Association of CYP2C19, CYP3A5 and GPIIb/IIIa gene polymorphisms with Aspirin and Clopidogrel Resistance in a cohort of Indian patients with Coronary Artery Disease.
BACKGROUND
Dual antiplatelet therapy with clopidogrel and aspirin is the current standard of care in the management of patients with coronary artery disease (CAD) and acute coronary syndrome (ACS). The variability in response to these antiplatelet agents may be due to the underlying genetic diversity. This study was designed to determine the resistance to aspirin and clopidogrel in Indian patients and to look for correlation, if any, with selected polymorphisms.


METHODS
Platelet function testing by light transmission aggregometry was performed on 72 patients with CAD/ACS who were stable on dual antiplatelet therapy (clopidogrel 75 mg OD and aspirin 150 mg OD) along with 72 controls. Aspirin resistance was considered as mean platelet aggregation ≥ 70% with 10 μm ADP and ≥ 20% with 0.75 mm arachidonic acid. Clopidogrel resistance was defined as <10% decrease from the baseline in platelet aggregation in response to ADP 10 μm and semi-response as <30% decrease from the baseline. Polymorphisms CYP2C19*2, *3, CYP3A5*3 and PLA1/A2 were genotyped.


RESULTS
We found 51.4% patients with inadequate response to clopidogrel (1.4% resistant and 50% semi-responders) and 5.5% patients semi-responders to aspirin, none being completely resistant. The genotype and allele frequencies of CYP2C19*2 and PLA1/A2 gene polymorphisms were significantly different between clopidogrel semi-responders and responders. Carriers of CYP2C19*2 and CYP3A5*3 showed diminished inhibition of platelet aggregation. No significant correlation was found between coronary events, type of coronary intervention with clopidogrel nonresponsiveness.


CONCLUSIONS
Unlike aspirin, a high proportion of partial responders to clopidogrel were identified. In an interim analysis on 72 Indian patients, a significant association was found between CYP2C19*2 and PLA1/A2 in clopidogrel semi-responders.
Department of Haematology, Sir Ganga Ram Hospital, New Delhi, India.
V
V
Arya
Department of Cardiology, Sir Ganga Ram Hospital, New Delhi, India.
P
P
Mahajan
Department of Haematology, Sir Ganga Ram Hospital, New Delhi, India.
A
A
Saraf
Department of Cardiology, Sir Ganga Ram Hospital, New Delhi, India.
A
A
Mohanty
Department of Cardiology, Sir Ganga Ram Hospital, New Delhi, India.
J P S
JP
Sawhney
Department of Haematology, Sir Ganga Ram Hospital, New Delhi, India.
M
M
Bhargava
D000368:Aged; D000483:Alleles; D016824:Antigens, Human Platelet / Q000235:genetics; D001241:Aspirin / Q000008:administration & dosage / Q000627:therapeutic use*; D016022:Case-Control Studies; D000077144:Clopidogrel; D015331:Cohort Studies; D015897:Comorbidity; D003324:Coronary Artery Disease / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics*; D065731:Cytochrome P-450 CYP2C19 / Q000235:genetics*; D051544:Cytochrome P-450 CYP3A / Q000235:genetics*; D004351:Drug Resistance / Q000235:genetics*; D005260:Female; D005838:Genotype; D006801:Humans; D007194:India; D039661:Integrin beta3; D008297:Male; D008875:Middle Aged; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000235:genetics*; D011110:Polymorphism, Genetic; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors; D013988:Ticlopidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use; D016896:Treatment Outcome
D016824:Antigens, Human Platelet; C061248:ITGB3 protein, human; D039661:Integrin beta3; D010975:Platelet Aggregation Inhibitors; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; C083451:human platelet antigen 1b; D000077144:Clopidogrel; D065731:Cytochrome P-450 CYP2C19; D051544:Cytochrome P-450 CYP3A; D013988:Ticlopidine; D001241:Aspirin
Drug Resistance; aspirin; clopidogrel; gene; molecular genetics; platelets; polymorphisms