title: Single nucleotide polymorphism of CYP3A5*3 contributes to clopidogrel resistance in coronary artery disease patients among Tamilian population.
abstract: Clopidogrel is an antiplatelet drug. It is used for the treatment as well as for the prophylaxis of coronary artery disease. Clopidogrel resistance is an emerging problem in clinical settings. The aim of the present study was to evaluate the effect of CYP3A5*3 genetic polymorphism on clopidogrel resistance. One hundred and forty-seven patients from outpatient Department of Cardiology on 75 mg/day of clopidogrel as maintenance dose were recruited from April 2010 to July 2011. All subjects gave written informed consent to participate in the study. DNA extraction was performed using phenol chloroform extraction procedure and genotyping by standard Taqman based RT-PCR method. Platelet aggregation was done at the end of 7th and 14th day by using chronolog lumi Aggregometer which is expressed as impedance in ohms. Impedance values of >5 ohms at the end of 6 min were considered as clopidogrel resistance. Subjects (N = 147) were analysed for CYP3A5*3 polymorphism, of which 49 (33%) were found to be clopidogrel resistant. Homomutants of CYP3A5*3 gene had 2.78 (0.97-7.98; p < 0.05) fold risk and heteromutants had 2.4 (0.93-6.46; p < 0.05) fold risk of developing clopidogrel resistance. Carriers of defective allele G of CYP3A5*3 had higher propensity to cause clopidogrel resistance with an odds ratio of 1.63. Variant alleles and genotypes of CYP3A5*3 polymorphism contributed significantly to clopidogrel resistance with a higher odds ratio. Thus, pharmacogenomics paves way for the emergence of stratified medicine in clopidogrel therapy and personalised pharmacotherapy in ischaemic heart disease.
authors.affiliation: Pharmacogenomics Laboratory, Department of Pharmacology, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Puducherry, 605 006, India, shalipriya85@gmail.com.
authors.forename: Rajendran
authors.initials: R
authors.lastname: Priyadharsini
authors.forename: Deepak Gopal
authors.initials: DG
authors.lastname: Shewade
authors.forename: Kumaresan
authors.initials: K
authors.lastname: Subraja
authors.forename: Byrappa Kempalalakshmamma
authors.initials: BK
authors.lastname: Ravindra
authors.forename: Gurusamy
authors.initials: G
authors.lastname: Umamaheswaran
authors.forename: Steven Aibor
authors.initials: SA
authors.lastname: Dkhar
authors.forename: Santhosh
authors.initials: S
authors.lastname: Satheesh
authors.forename: Magadi Gopalakrishna
authors.initials: MG
authors.lastname: Sridhar
authors.forename: Sunil K
authors.initials: SK
authors.lastname: Narayan
authors.forename: Chandrasekaran
authors.initials: C
authors.lastname: Adithan
mesh_terms: D000077144:Clopidogrel; D003324:Coronary Artery Disease / Q000188:drug therapy* / Q000235:genetics*; D051544:Cytochrome P-450 CYP3A / Q000235:genetics*; D004351:Drug Resistance / Q000235:genetics*; D005006:Ethnicity / Q000235:genetics*; D006801:Humans; D007194:India; D010597:Pharmacogenetics / Q000379:methods; D010974:Platelet Aggregation / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013988:Ticlopidine / Q000031:analogs & derivatives*
chemical_list: D000077144:Clopidogrel; D051544:Cytochrome P-450 CYP3A; D013988:Ticlopidine