title: Enhanced clopidogrel responsiveness in smokers: smokers' paradox is dependent on cytochrome P450 CYP1A2 status.
abstract: OBJECTIVE
  Observational studies have reported enhanced response to clopidogrel in smokers (the smokers' paradox). We examined whether genetic variations in the cytochrome and drug transporter system are associated with the effect of smoking on clopidogrel response.
  
  
  RESULTS
  Clopidogrel on-treatment platelet reactivity (OPR) was measured in 1431 consecutive patients who underwent coronary angiography. Gene samples were available and genotyping was successful in 1123 patients. Nine candidate single-nucleotide polymorphisms in 5 cytochrome genes and 1 drug transporter gene were assessed. The mean OPR of the entire population was 241.9 ± 79.3 (P2Y(12) reaction units). Two hundred forty-nine (17%) smokers had lower OPR compared with 1182 (83%) nonsmokers (227.6 ± 76.0 versus 244.9 ± 79.7, P=0.001). Among the 9 single-nucleotide polymorphisms, only CYP1A2 showed a genotype-dependent change in the effect of smoking on OPR. After adjustment for possible confounding factors, cigarette smoking was associated with a lower OPR by -19 P2Y(12) reaction units (P=0.009) and lower risk for high OPR (odds ratio [OR], 0.48; 95% CI, 0.31 to 0.74) in the AA and CA genotypes but not in the CC genotype.
  
  
  CONCLUSIONS
  Enhanced clopidogrel response in smokers, known as the smokers' paradox, is not universal but was observed only in cytochrome P450 CYP1A2 (-163C>A) A-allele carriers, suggesting a genotype-dependent effect of smoking on clopidogrel responsiveness.
authors.affiliation: Department of Internal Medicine and Cardiovascular Center, Seoul National University Hospital, Seoul, Korea.
authors.forename: Kyung Woo
authors.initials: KW
authors.lastname: Park
authors.forename: Jin Joo
authors.initials: JJ
authors.lastname: Park
authors.forename: Ki-Hyun
authors.initials: KH
authors.lastname: Jeon
authors.forename: Si-Hyuk
authors.initials: SH
authors.lastname: Kang
authors.forename: Il-Young
authors.initials: IY
authors.lastname: Oh
authors.forename: Han-Mo
authors.initials: HM
authors.lastname: Yang
authors.forename: Hyun-Jai
authors.initials: HJ
authors.lastname: Cho
authors.forename: Hae-Young
authors.initials: HY
authors.lastname: Lee
authors.forename: Hyun-Jae
authors.initials: HJ
authors.lastname: Kang
authors.forename: Bon-Kwon
authors.initials: BK
authors.lastname: Koo
authors.forename: Byung-Hee
authors.initials: BH
authors.lastname: Oh
authors.forename: Young-Bae
authors.initials: YB
authors.lastname: Park
authors.forename: Hyo-Soo
authors.initials: HS
authors.lastname: Kim
mesh_terms: D000368:Aged; D016009:Chi-Square Distribution; D000077144:Clopidogrel; D003430:Cross-Sectional Studies; D019388:Cytochrome P-450 CYP1A2 / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D016014:Linear Models; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D016017:Odds Ratio; D010641:Phenotype; D015539:Platelet Activation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000627:therapeutic use*; D010979:Platelet Function Tests; D020641:Polymorphism, Single Nucleotide; D011446:Prospective Studies; D058925:Receptors, Purinergic P2Y12 / Q000097:blood / Q000187:drug effects; D056910:Republic of Korea; D018570:Risk Assessment; D012307:Risk Factors; D012907:Smoking / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D013988:Ticlopidine / Q000031:analogs & derivatives* / Q000627:therapeutic use
chemical_list: C548576:P2RY12 protein, human; D010975:Platelet Aggregation Inhibitors; D058925:Receptors, Purinergic P2Y12; D000077144:Clopidogrel; C504573:CYP1A2 protein, human; D019388:Cytochrome P-450 CYP1A2; D013988:Ticlopidine