A synergic effect between CYP2C19*2, CYP2C19*3 loss-of-function and CYP2C19*17 gain-of-function alleles is associated with Clopidogrel resistance among Moroccan Acute Coronary Syndromes patients
Hassani Idrissi et al. BMC Res Notes
A synergic effect between CYP2C19*2, CYP2C19*3 loss-of-function and CYP2C19*17 gain-of-function alleles is associated with Clopidogrel resistance among Moroccan Acute Coronary Syndromes patients
Hind Hassani Idrissi 0
Wiam Hmimech 0
Nada El Khorb 1
Hafid Akoudad 1
Rachida Habbal 2
Sellama Nadifi 0
0 Laboratory of Genetics and Molecular Pathology, Medical School, University Hassan II , Casablanca , Morocco
1 Department of Cardiology, University Hospital Center Hassan II , Fes , Morocco
2 Department of Cardiology, University Hospital Center Ibn Rochd , Casablanca , Morocco
Objective: The main objective of our study was to investigate the association of CYP2C19*2 and CYP2C19*3 lossof-function and CYP2C19*17 gain-of-function variants of CYP2C19 gene with Clopidogrel resistance in a sample of Moroccan Acute Coronary Syndromes patients. Results: Our results showed the existence of a synergic effect between the three alleles, statistically very significant, on Clopidogrel resistance among the treated patients (P = 0.0033). For the three variants of the CYP2C19 gene, the heterozygous and homozygous mutant genotypes were the most frequent among ACS patients (CYP2C19*2: 82.76% GA and 10.35% AA; CYP2C19*3: 76.67% GA and 18.33% AA; CYP2C19*17: 66.67% CT and 18.66% TT). Allelic frequencies were 51.73% vs 48.27% (P < 0.001); 56.67% vs 43.33% (P < 0.001); and 52% vs 48% (P = 0.01) for the mutant and wild type alleles of the CYP2C19*2, CYP2C19*3 and CYP2C19*17 variants respectively. Our results support a role of CYP2C19 gene variants as a potential marker of Clopidogrel response. Understanding the functional and clinical consequences of these variants may help for treating patients more effectively, they could be genetically screened and appropriate dose adjustments could be made on the basis of their CYP2C19 genotype.
Acute Coronary Syndromes; Clopidogrel response; CYP2C19*2; CYP2C19*3; CYP2C19*17; Moroccan population
Prescribed as dual antiplatelet therapy with aspirin,
Clopidogrel is an antiplatelet agent used as a basic
treatment among patients with Acute Coronary Syndromes
(ACS) or undergoing percutaneous coronary
intervention (PCI) [
]. Although its widely described
effectiveness, Clopidogrel exhibits a large inter-individual
variability of response [
]. Multiple factors may
influence the pharmacokinetic and pharmacodynamic effects
of the molecule, by affecting its intestinal absorption
[SNPs of the multi drug resistance 1 (MDR1) gene] [
metabolism (SNPs of the hepatic Cyp450 isoenzymes), or
preventing its effect on its direct target, the P2Y12
Clopidogrel is administrated as an inactive prodrug
that requires several biotransformation steps in order
to be active. This process takes place via two
sequential hepatic reactions of oxidation, catalyzed by the
Cytochrome P450 (CYP450) system [
] especially the
CYP2C19 located on chromosome 10 (10q24.1–q24.3)
CYP2C19 is a highly polymorphic locus, with almost
27 variants currently reported, from which only three are
with normal activity and one with high activity, the others
are with no enzymatic activity [
]. The most described
CYP2C19 abnormal variants are CYP2C19*2 (681G/A)
and CYP2C19*3 (636G/A), which account for about 99%
of all the poor metabolizers (PM) in the Asian population
and 87% in the Caucasian population [
variants lead respectively to the creation of a splicing defect
and stop codon, and therefore to nonfunctional proteins,
resulting in impaired metabolism of CYP2C19 substrates
such as Clopidogrel [
]. The substitution of G681A in
exon 5 of CYP2C19*2 variant allele creates an aberrant
splice site resulting in an alteration of the reading frame
of mRNA and consequently a truncated nonfunctional
protein. Data from several studies have reported that
individuals carrying the CYP2C19*2 allele have impaired
pharmacodynamic response to different Clopidogrel doses, as
showed with the different platelet function assays used.
The CYP2C19*2 allele frequencies vary from ~ 15% among
Caucasians and Africans, to ~ 29–35% among Asians
]. The substitution of G636A in exon 4 of CYP2C19*3
allele results in a premature stop codon, which is
common in oriental populations but very rare in Caucasians.
Poor metabolizers (PM) of CYP2C19 represent
approximately 3–5% of Caucasians. Higher frequencies of PMs
(13–23%) are found in most Asian populations [
Conversely, CYP2C19*17 allele (c.− 806C>T; rs12248560) was
found to be associated with increased CYP2C19
transcription resulting in a modest gain of function. This variant
is relatively common, with an average multi-ethnic allele
frequency of ~ 3–21%. The study of Alain Li-Wan-Po
and co-workers [
] reported that CYP2C19*17 effect is
unlikely to have clinical significance except for drugs with
very narrow therapeutic indices, such as Clopidogrel. Even
then, only mutant homozygous of the variant are likely to
be at significantly increased risk.
In 2009, the US Food and Drug Administration (FDA)
stated that polymorphisms in CYP2C19 may be
considered as significant and independent predictors of
Clopidogrel pharmacokinetics, pharmacodynamics
and clinical response [
]. Generally, on the basis of
CYP2C19 genotyping, patients are classified as ultra
rapid metabolizers (UMs) if they carry double copy of the
GOF allele *17 (*17/*17), extensive metabolizers (EMs) if
they carry double copy of the wild type allele *1 (*1/*1),
intermediate metabolizers (IMs) when carrying one copy
of the normal allele and one of the deficient one (*1/*2;
*1/*3), or one copy of a deficient allele and one GOF allele
(*2/*17, *3/*17), and poor metabolizers (PMs) when
carrying double copy of a deficient allele (*2/*2; *3/*3) or two
copies of two deficient alleles (*2/*3) [
]. As the
Clopidogrel effectiveness depends essentially on its activation
by CYP2C19, therapeutic recommendations based on
CYP2C19 genotyping were published [
recommending the use of an alternative antiplatelet agent
(prasugrel or ticagrelor, if no contraindication) among PMs and
IMs patients, as they have reduced platelet inhibition,
increased residual platelet aggregation, increased risk for
adverse cardiovascular events [
As there is lack of data concerning the genetic bases
of Clopidogrel resistance among ACS patients in North
African populations in general and Moroccan one
specifically, the main objective of our case–control study is
to investigate, for the first time in Morocco, whether or
not the CYP2C19*2, CYP2C19*3 loss-of-function and
CYP2C19*17 gain-of-function alleles are associated with
the inter-individual variability of response to Clopidogrel,
among a sample of Moroccan ACS patients.
75 Moroccan ACS patients were recruited from the
department of Cardiology, University hospital center
Hassan II, Fes, Morocco. Details of patients’ recruitment,
study design, DNA extraction and CYP2C19 genotyping
are reported in Additional file 1.
Characteristics of the studied population
The studied sample was predominantly composed of
around 57 years of age Arabian males (56%; 57 ± 9.72)
(Additional file 2: Table S1). Routine pathology data of
our patients are represented in (Additional file 3: Table
S2): 68.96% of them were under PPI.
Verify‑now test results vs patients’ baseline characteristics and clinical features
A correlation was held between the verify-now test
results (resistant/non-resistant patients) and the patients’
baseline characteristics and clinical features (Additional
file 3: Table S3): 100% of the resistant group were female
with a statistically significant association with the
parameter ‘Gender’ (P = 0.01). A potential trend to a
statistical association was also found with ‘Smoking’ and ‘HTA’
parameters (P = 0.07 and 0.09 respectively).
Clinical data vs polymorphisms’ distribution
A second correlation was held between patients’
clinical features and the distribution of the 681G>A (*2), 636
G>A (*3) and − 806 C>T (*17) polymorphisms of the
CYP2C19 gene (Table 1). Patients with personal
antecedents presented higher frequency of the CYP2C19*17
mutant allele than those with no personal antecedents
(P = 0.002). No other particular trend was observed
(P > 0.05).
ACS subtypes vs polymorphisms’ distribution
Patients were stratified on the basis of the ACS subtype
they present (ST+/ST−) and correlated to the
polymorphisms distribution, as shown in (Table 2). A statistically
significant association between ST+ group and the *2
and *3 mutant alleles (P = 0.002 and 0.04 respectively),
but not the *17 one.
Verify‑now test results vs co‑presence of the deficient alleles
The same stratification was held this time with the
verifynow test results (Additional file 5: Table S4). No
particular trend was observed with the alleles taken individually
(P > 0.05).
CYP2C19 alleles are inherited as autosomal
codominant traits, allowing assigning every patient to a
ST (+): Acute Coronary Syndromes with ST segment elevation; ST (−): Acute Coronary Syndromes without ST segment elevation
*Statistically significant (Chi square test)
Clopidogrel metabolizer phenotype, according to the
identified CYP2C19 genotype. In this context, to study
the potential synergic effect of the three polymorphisms
on Clopidogrel resistance, patients were classified into
three groups A, B and C, on the basis of the co-presence
of the deficient alleles:
• A group (ultra-rapid metabolizers): *17/*17; *1/*17.
• B group (intermediate metabolizers): *1/*2; *1/*3;
• C group (poor metabolizers): *2/*2; *3/*3; *2/*3.
All the resistant patients were carrying at least one
copy of a loss-of-function (LOF) allele of the CYP2C19
gene, with 40% carrying one copy of the *2 or *3 mutant
alleles, and 60% with two copies of the LOF alleles *2
and *3; the association was very statistically significant
(P = 0.003) (Table 3). Based on CYP2C19 metabolizer
profile knowledge and the role of the coded enzyme in
Clopidogrel activation, Ums and EMs are expected to
have adequate levels of the active metabolite and
effective platelet inhibition, while PMs are predicted to have
decreased levels of the active metabolite and increased
on-treatment platelet aggregation; for IMs, response to
Clopidogrel still falling somewhere in between.
Allelic and genotypic distribution of the CYP2C19 polymorphisms
As shown in (Additional file 6: Table S5), the three
mutant alleles *2; *3 and *17 were the most frequent
among patients (51.73, 56.67 and 52% respectively),
increasing, thus, the association with these
polymorphisms with the pathology.
In the present study, we tried to evaluate the
potential modulating effect of *2, *3 and *17 allelic variants of
CYP2C19 gene, on Clopidogrel resistance among
Moroccan ACS patients. Our results suggested that, taken
individually, no one of the three alleles showed statistical
association with Clopidogrel resistance (P > 0.05).
However, we found a synergic effect between the three alleles,
statistically very significant, on Clopidogrel resistance
among the treated patients (P = 0.0033).
Several subsequent studies support the positive
relationship between CYP2C19 variants and platelet
responsiveness to Clopidogrel [
]. The study of Hulot
et al. , consisting of 28 healthy subjects, followed for
7 days of 75 mg/day of Clopidogrel, showed that, of all
the alleles analyzed, only *2 LOF was positively correlated
with decreased platelet responsiveness to Clopidogrel.
Similarly, Umemura and co-workers performed a study
on 47 healthy Asian volunteers, suggesting a determining
effect of CYP2C19 pharmacogenomic status on the
conversion of Clopidogrel to its active metabolite [
Another study called PAPI, for pharmacogenomics of
anti-platelet intervention, performed on a sample of 420
healthy Amish volunteers, exposed for 1 week to
Clopidogrel, showed that the response to Clopidogrel diverged
between the recruited subjects, with 70% of estimated
heritability of Clopidogrel response, as the participant
were related though a 14 generation pedigree. This
interindividual variability in response between healthy
individuals was partially explained by a number of studies
suggesting a major effect of CYP2C19 variants, especially
*2, on decreased Clopidogrel’ active metabolite
formation and increased residual on-treatment platelet
reactivity, resulting in poor clinical outcomes and increased risk
of complications development [
Even the association of CYP2C19 polymorphisms
with platelet responsiveness to Clopidogrel was largely
approved among ACS/PCI patients, the association
among patients under Clopidogrel for other indications
(e.g. stable angina and arterial fibrillation), have been
declared negative [
]. Many authors have explained
this inconsistency by the fact that the CYP2C19 effect
size on Clopidogrel effectiveness may parallel the effect
of this molecule for a given clinical indication; high in
patients at high risk for recurrent CVD events in the
absence of adequate anti platelet therapy (e.g., ACS/PCI),
and low or non-existent for clinical situations where the
drug has reduced effect on cardiovascular outcomes (e.g.,
stable angina, atrial fibrillation and peripheral vascular
]. Thus, CYP2C19
genotyping/Clopidogrel is an example of indication-specific
As the Clopidogrel effectiveness depends essentially on
its activation by CYP 450 enzymes, especially CYP2C19,
therapeutic recommendations based on CYP2C19
genotyping were published: a statement from the US Food and
Drug Administration (FDA) reported that Clopidogrel
has reduced effectiveness among CYP2C19 PMs, and
that, in their case, alternative treatment or therapeutic
strategy should be adopted, as they exhibit higher
cardiovascular complications rates than do patients having
normal CYP2C19 activity [
]. In addition to that, standard
doses of Clopidogrel, as found in the product insert, are
warranted in ACS/PCI patients predicted to be
extensive or ultrarapid metabolizers (i.e., *1/*1, *1/*17, and
*17/*17). For patient predicted to be PM (i.e., *2/*2) as
well as the IMs ones, the use of an alternative antiplatelet
agent (e.g., prasugrel or ticagrelor) was supported by The
Clinical Pharmacogenetics Implementation Consortium
(CPIC) statement, when not clinically contraindicated
With the adoption of alternative anti-platelet therapies
for genetically predisposed patients toward inadequate
response, the promise of translating these
pharmacogenetic insights into more effective individualized
anti-platelet therapy is sparking more excitement and
optimism for the future of personalized medicine [
Despite a large body of evidence supporting clinical
utility, adoption of anti-platelet pharmacogenetics into
clinical practice remains slow. Many studies suggest a
link between CYP2C19 polymorphisms and Clopidogrel
resistance. This is providing the basis for
genotypeinformed therapeutic recommendations and optimal
individualized antiplatelet treatment, in order to reduce
the risk of recurrent CV events and adverse effects
such as bleeding, when considering treatment with
Our study is the first to investigate the potential
association of CYP2C19 polymorphisms with Clopidogrel
resistance among ACS patients in Moroccan
population. Our results support a role of LOF variants in
the CYP2C19 gene as a major marker of Clopidogrel
response in Morocco. However, some limitations are to
be mentioned, such us the small sample size of patients,
the lack of Clopidogrel active metabolite dosing and
correlation of SNPs with secondary cardiovascular events.
More studies including larger sample sizes and focusing
on these points may provide useful help to better
understand the phenomenon of Clopidogrel heterogeneity of
Additional file 1: Table S1. Demographic data of the 75 ACS patients.
Additional file 2: Table S2. Routine pathology data of our ACS patients.
Additional file 3: Table S3. Baseline characteristics of the ACS patients
Vs Verify-Now test results.
Additional file 4: Table S4. Verify-Now test results Vs polymorphisms
Additional file 5: Table S5. Genotypic and allelic distribution among the
studies sample of patients.
Additional file 6. Details of the patients’ recruitment, study design and
ACS: Acute Coronary Syndrome; LOF: loss of function; SNP: single nucleotide
polymorphism; RFLP: restriction fragment length polymorphism.
HHI drafted the manuscript, carried out the DNA extraction and the molecular
genetic studies, and performed the statistical analysis. HW participated in the
interpretation of data. NELK carried out the patient recruitment and the
clinical data collection. HA, HR and NS designed and coordinated the experiments;
they are the directors of the study. All authors read and approved the final
The authors declare that they have no competing interests.
Availability of data and materials
All data generated or analyzed during this study are included in this published
article (and its Additional files).
Consent for publication
Ethics approval and consent to participate
The present study was approved by the local Ethics Committee of University
Hassan II, school of medicine and pharmacy, Casablanca, Morocco; all the
participants have accepted and signed the informed consent.
Springer Nature remains neutral with regard to jurisdictional claims in
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1. King SB III, Smith SC Jr, Hirshfeld JW Jr, Jacobs AK , Morrison DA , Williams DO , 2005 WRITING COMMITTEE MEMBERS, Feldman TE , Kern MJ , O'Neill WW , Schaff HV , Whitlow PL , Adams CD , Anderson JL , Buller CE , Creager MA , Ettinger SM , Halperin JL , Hunt SA , Krumholz HM , Kushner FG , Lytle BW , Nishimura R , Page RL , Riegel B , Tarkington LG , Yancy CW . Focused update of the ACC/AHA/SCAI 2005 guideline update for percutaneous coronary intervention: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines: 2007 writing group to review new evidence and update the ACC/ AHA/SCAI 2005 guideline update for percutaneous coronary intervention, writing on behalf of the 2005 Writing Committee . Circulation . 2007 ; 2008 (117): 261 - 95 .
2. Kushner FG , Hand M , Smith SC Jr, King SB III, Anderson JL , Antman EM , Bailey SR , Bates ER , Blankenship JC , Casey DE Jr, Green LA , Hochman JS , Jacobs AK , Krumholz HM , Morrison DA , Ornato JP , Pearle DL , Peterson ED , Sloan MA , Whitlow PL , Williams DO , American College of Cardiology Foundation, American Heart Association Task Force on Practice Guidelines. Focused updates: ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction (updating the 2004 guideline and 2007 focused update) and ACC/AHA/SCAI guidelines on percutaneous coronary intervention (updating the 2005 guideline and 2007 focused update): a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines . Circulation . 2009 ; 2009 (120): 2271 - 306 .
3. Gurbel PA , Bliden KP , Hiatt BL , O'Connor CM . Clopidogrel for coronary stenting: response variability, drug resistance, and the effect of pretreatment platelet reactivity . Circulation . 2003 ; 107 : 2908 - 13 .
4. Mallouk N , Labruyere C , Reny JL , Chapelle C , et al. Prevalence of poor biological response to clopidogrel: a systematic review . Thromb Haemost . 2012 ; 107 ( 3 ): 494 - 506 .
5. Mega JL , Close SL , Wiviott SD , Shen L , Walker JR , Simon T , Antman EM , Braunwald E , Sabatine MS . Genetic variants in ABCB1 and CYP2C19 and cardiovascular outcomes after treatment with Clopidogrel and prasugrel in the TRITON-TIMI 38 trial: a pharmacogenetic analysis . Lancet . 2010 ; 376 : 1312 - 29 .
6. Idrissi Hassani H , Hmimech W , El Khorb N , Akoudad H , Habbal R , et al. Association of the C3435T multi-drug resistance gene-1 (MDR-1) polymorphism with clopidogrel resistance among Moroccan Acute Coronary Syndromes (ACS) patients . J Thromb Circ . 2016 ; 2 : 115 .
7. Shalia KK , Shah VK , Pawar P , Divekar SS , Payannavar S. Polymorphisms of MDR1, CYP2C19 and P2Y12 genes in Indian population: effects on clopidogrel response . Indian Heart J . 2013 ; 65 : 158 - 67 .
8. Hassani Idrissi H , Hmimech W , El Khorb N , Akoudad H , Habbal R , et al. Does i-T744C P2Y12 polymorphism modulate clopidogrel response among Moroccan Acute Coronary Syndromes (ACS) patients . Genet Int J . 2017 . https://doi.org/10.1155/ 2017 /9532471.
9. Pereillo JM , Maftouh M , Andrieu A , Uzabiaga MF , Fedeli O , Savi P , Pascal M , Herbert JM , Maffrand JP , Picard C . Structure and stereochemistry of the active metabolite of clopidogrel . Drug Metab Dispos . 2002 ; 30 : 1288 - 95 .
10. Savi P , Pereillo JM , Uzabiaga MF , Combalbert J , Picard C , Maffrand JP , Pascal M , Herbert JM . Identification and biological activity of the active metabolite of clopidogrel . Thromb Haemost . 2000 ; 84 : 891 - 6 .
11. Dean L . Clopidogrel therapy and CYP2C19 genotype . In: Pratt V , McLeod H , Dean L , et al., editors. Medical genetics summaries. Bethesda: National Center for Biotechnology Information (US) ; 2012 (Updated 2015 Nov 19 ).
12. Harmsze AM , van Werkum JW , Ten Berg JM , Zwart B , Bouman HJ , Breet NJ , van't Hof AW , Ruven HJ , Hackeng CM , Klungel OH , de Boer A. CYP2C19*2 and CYP2C9*3 alleles are associated with stent thrombosis: a case-control study . Eur Heart J . 2010 ; 31 : 3046 - 53 .
13. Human gene CYP2C19 Description and Page Index . http://genome. ucscedu/cgibin/hgGene?hgg _gene=L07093&hgg_prot=Q767A3_ HUMAN&hg_chrom=chr10&hgg_start=96437900&hgg_ end=96602820&hgg_type=knownGene&db=hg18&hg sid=76270719%20TITLE . Accessed July 2017 .
14. Online Mendelian Inheritance in Man. www.ncbi.nlm.nih.gov/entrez/ dispomim.cgi? id=124020. Accessed July 2017 .
15. Scott SA , Sangkuhl K , Stein CM , Hulot JS , et al. Clinical Pharmacogenetics Implementation Consortium guidelines for CYP2C19 genotype and clopidogrel therapy: 2013 update . Clin Pharmacol . 2013 ; 94 ( 3 ): 317 - 23 .
16. Herman D , Dolžan V , Breskvar K. Genetic polymorphism of cytochromes p450 2C9 and 2C19 in Slovenian population . Zdravvestn . 2003 ; 72 : 347 - 51 .
17. Li-Wan-Po A , Girard T , Farndon P , Cooley C , Lithgow J . Pharmacogenetics of CYP2C19: functional and clinical implications of a new variant CYP2C19*17 . Br J Clin Pharmacol . 2010 . https://doi. org/10.1111/j.1365- 2125 . 2009 . 03578 .x.
18. Perry CG , Shuldiner AR . Pharmacogenomics of anti-platelet therapy: how much evidence is enough for clinical implementation ? J Hum Genet . 2013 ; 58 ( 6 ): 339 - 45 . https://doi.org/10.1038/jhg. 2013 .41.NI.
19. Furuta T , Sagehashi Y , Shirai N , Sugimoto M , Nakamura A , Kodaira M , Kenmotsu K , Nagano M , Egashira T , Ueda K , Yoneyama M , Ohashi K , Ishizaki T , Hishida A . Influence of CYP2C19 polymorphism and Helicobacter pylori genotype determined from gastric tissue samples on response to triple therapy for H pylori infection . Clin Gastroenterol Hepatol . 2005 ; 3 ( 6 ): 564 - 73 .
20. Fontana P , Hulot JS , De Moerloose P , Gaussem P . Influence of CYP2C19 and CYP3A4 gene polymorphisms on clopidogrel responsiveness in healthy subjects . J Thromb Haemost . 2007 ; 5 : 2153 - 5 .
21. Simon T , et al. Genetic polymorphisms and the impact of a higher clopidogrel dose regimen on active metabolite exposure and antiplatelet response in healthy subjects . Clin Pharmacol Ther . 2011 ; 90 : 287 - 95 .
22. Hulot JS , et al. Cytochrome P450 2C19 loss-of-function polymorphism is a major determinant of clopidogrel responsiveness in healthy subjects . Blood . 2006 ; 108 : 2244 - 7 .
23. Umemura K , Furuta T , Kondo K. The common gene variants of CYP2C19 affect pharmacokinetics and pharmacodynamics in an active metabolite of clopidogrel in healthy subjects . J Thromb Haemost . 2008 ; 6 : 1439 - 41 .
24. Lewis J , et al. The CYP2C19*17 variant is not independently associated with clopidogrel response . J. Thromb Haemost . 2013 ; 11 ( 9 ): 1640 - 6 (epub ahead of print 29 June 2013 ).
25. Simon T , et al. Genetic determinants of response to clopidogrel and cardiovascular events . N Engl J Med . 2009 ; 360 : 363 - 75 .
26. Sibbing D , et al. Cytochrome P450 2C19 loss-of-function polymorphism and stent thrombosis following percutaneous coronary intervention . Eur Heart J . 2009 ; 30 : 916 - 22 .
27. Pare G , et al. Effects of CYP2C19 genotype on outcomes of clopidogrel treatment . N Engl J Med . 2010 ; 363 : 1704 - 14 .
28. Brandt JT , et al. Common polymorphisms of CYP2C19 and CYP2C9 affect the pharmacokinetic and pharmacodynamic response to clopidogrel but not prasugrel . J Thromb Haemost . 2007 ; 5 : 2429 - 36 .
29. Giusti B , et al. Cytochrome P450 2C19 loss-of-function polymorphism, but not CYP3A4 IVS10+ 12G/A and P2Y12 T744C polymorphisms, is associated with response variability to dual antiplatelet treatment in high-risk vascular patients . Pharmacogenet Genom . 2007 ; 17 : 1057 - 64 .
30. Collet JP , et al. Cytochrome P450 2C19 polymorphism in young patients treated with clopidogrel after myocardial infarction: a cohort study . Lancet . 2009 ; 373 : 309 - 17 .
31. Roden DM . Cardiovascular pharmacogenomics: the future of cardiovascular therapeutics? Can J Cardiol . 2013 ; 29 ( 1 ): 58 - 66 . https://doi. org/10.1016/j.cjca. 2012 . 07 .845.
32. Shuldiner AR , et al. Association of cytochrome P450 2C19 genotype with the antiplatelet effect and clinical efficacy of clopidogrel therapy . JAMA . 2009 ; 302 : 849 - 57 .
33. Bhatt DL , et al. The relationship between CYP2C19 polymorphisms and ischaemic and bleeding outcomes in stable outpatients: the CHARISMA genetics study . Eur Heart J . 2012 ; 33 : 2143 - 50 .
34. Johnson JA , et al. Clopidogrel: a case for indication-specific pharmacogenetics . Clin Pharmacol Ther . 2012 ; 91 : 774 - 6 .
35. Swen JJ , Nijenhuis M , de Boer A , Grandia L , et al. Pharmacogenetics: from bench to byte- an update of guidelines . Clin Pharmacol Ther . 2011 ; 89 ( 5 ): 662 - 73 .