title: Meta-analyses of the association between cytochrome CYP2C19 loss- and gain-of-function polymorphisms and cardiovascular outcomes in patients with coronary artery disease treated with clopidogrel.
abstract: OBJECTIVE
  To perform a meta-analysis of the association between CYP2C19 loss- and gain-of-function variants and cardiovascular outcomes and bleeding in patients with coronary artery disease treated with clopidogrel, and to explore the causes of heterogeneity between studies.
  
  
  METHODS
  A comprehensive literature search was conducted. A random-effects model was used to summarise the results. In the presence of between-study heterogeneity, a meta-regression analysis was performed to identify study characteristics explaining this heterogeneity.
  
  
  RESULTS
  Patients who carried a loss-of-function allele, mainly CYP2C19*2, did not present an increased risk of a cardiovascular event, HR =1.23 (95% CI 0.97 to 1.55). Substantial heterogeneity was observed between studies (I(2) =35.6), which was partially explained by the study sample size: the pooled HR was higher among studies with a sample size <500 patients (HR =3.55; 95% CI 1.66 to 7.56) and lower among studies with a sample size ≥500 (HR =1.06; 95% CI 0.89 to 1.26). CYP2C19*2 was associated with an increased risk of a stent thrombosis (HR =2.24; 95% CI 1.52 to 3.30). The gain-of-function allele, mainly CYP2C19*17, was associated with a lower risk of cardiovascular events (HR =0.75; 95% CI 0.66 to 0.87) and a higher risk of major bleeding (HR =1.26; 95% CI 1.05 to 1.50).
  
  
  CONCLUSIONS
  Not only CYP2C19 loss-of-function but also gain-of-function alleles should be considered to define the pharmacogenetic response to clopidogrel. The results question the relevance of the CYP2C19 loss-of-function alleles in the prediction of major cardiovascular events beyond stent thrombosis in coronary patients treated with clopidogrel. The gain-of-function variant is associated with a lower risk of cardiovascular events but a higher risk of bleeding.
authors.affiliation: Cardiovascular Epidemiology and Genetics, Institut de Recerca Hospital del Mar, Dr Aiguader 88, Barcelona, Catalonia, Spain.
authors.forename: Michel
authors.initials: M
authors.lastname: Zabalza
authors.forename: Isaac
authors.initials: I
authors.lastname: Subirana
authors.forename: Joan
authors.initials: J
authors.lastname: Sala
authors.forename: Carla
authors.initials: C
authors.lastname: Lluis-Ganella
authors.forename: Gavin
authors.initials: G
authors.lastname: Lucas
authors.forename: Marta
authors.initials: M
authors.lastname: Tomás
authors.forename: Rafel
authors.initials: R
authors.lastname: Masiá
authors.forename: Jaume
authors.initials: J
authors.lastname: Marrugat
authors.forename: Ramon
authors.initials: R
authors.lastname: Brugada
authors.forename: Roberto
authors.initials: R
authors.lastname: Elosua
mesh_terms: D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics* / Q000378:metabolism*; D000077144:Clopidogrel; D003324:Coronary Artery Disease / Q000188:drug therapy / Q000235:genetics*; D065731:Cytochrome P-450 CYP2C19; D005838:Genotype; D006470:Hemorrhage; D006801:Humans; D010597:Pharmacogenetics; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D011110:Polymorphism, Genetic; D012307:Risk Factors; D013988:Ticlopidine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D010975:Platelet Aggregation Inhibitors; D000077144:Clopidogrel; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D013988:Ticlopidine