|(A;A)||4||poor metabolizer of several popular medicines; patients prescribed Plavix get less benefit, and have higher risk for adverse cardiovascular events|
|(A;G)||3||poorer metabolizer of several popular medicines; patients prescribed Plavix get less benefit, and have higher risk for adverse cardiovascular events|
The risk allele is rs4244285(A).
As a nonfunctioning CYP2C19, this variant would be expected to be a poor metabolizer of several commonly prescribed drugs, including anti-ulcer drugs like omeprazole (trade names Losec and Prilosec), esomeprazole (trade name Nexium), and lansoprazole (trade name Prevacid).
In Caucasians, SNPs in CYP2C19 are relatively rare (in contrast to SNPs in CYP2D6), but SNPs in this gene are common in Asians. Ulcer treatment with omeprazole to reduce Helicobacter pylori has been shown to vary depending on a patient's CYP2C19 genotype, varying from 28% in patients homozygous for CYP2C19 alleles encoding fully functional proteins to 100% in patients with variations leading to poor metabolism. The fact that poor metabolizers for many cytochrome p450s achieve higher therapeutic success for some drugs is speculated to be because for some of the drug being broken down (ie metabolized) slower, the effective concentrations are both higher and longer lasting. [PMID 9867757]
However, other drugs clearly work less well in carriers of reduced function CYP2C19 alleles. An example of such a drug is clopidogrel, sold under the brand name Plavix. This has now (2010) been acknowledged by the FDA, who have added a boxed warning to Plavix, alerting patients and health care professionals that the drug can be less effective in people who have CYP2C19 variants and cannot convert the drug as effectively to its active form.
Several recent (December 2008) studies reach similar (though not identical) conclusions about the consequences of CYP2C19*2 allele carriers prescribed clopidogrel to reduce their cardiovascular risk:
- A study of 245 French patients under 45 years of age prescribed clopidogrel after surviving a first heart attack concluded that rs4244285(A) allele carriers were at 4x higher risk (CI: 1·81—9·02, p=0·0006) for subsequent adverse cardiovascular events compared to noncarriers.[PMID 19108880]
- A study of 2,208 French patients prescribed clopidogrel, of which 225 subsequently died and 94 had a nonfatal heart attack or stroke, came to two conclusions [PMID 19106083]:
- Patients carrying any two CYP2C19 loss-of-function alleles (*2, *3, *4, or *5), had about a 2x increased risk (21.5% vs. 13.3%; adjusted hazard ratio, 1.98; CI: 1.10-3.58) for adverse cardiovascular events than CYP2C19*1 homozygotes.
- Among the 1,535 patients who underwent percutaneous coronary intervention (angioplasty) during hospitalization, patients with two CYP2C19 loss-of-function alleles were at even higher risk for adverse events: 3.58x (CI: 1.71-7.51) compared to CYP2C19*1 homozygotes.
- A study of 1,477 subjects with acute coronary syndromes who were treated with clopidogrel as part of the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial Infarction (TRITON-TIMI) 38 study concluded that rs4244285(A) allele carriers had a 1.53x increased risk for death from cardiovascular causes, myocardial infarction, or stroke, as compared with noncarriers (12.1% vs. 8.0%; CI: 1.07-2.19, p=0.01) and were at 3x higher risk of stent thrombosis (2.6% vs. 0.8%; CI: 1.19-8.00, p=0.02). [PMID 19106084]
- CYP2C19*2 loss-of-function genotypes were associated with diminished platelet response to clopidogrel treatment and poorer cardiovascular outcomes in a study of 429 healthy Amish individuals treated for 7 days (in the first study) and 227 patients undergoing percutaneous coronary intervention (angioplasty) (in the second study). [PMID 19706858]
[PMID 17048007] Association of warfarin dose with genes involved in its action and metabolism.
[PMID 18521743] CYP2C19*17 is associated with decreased breast cancer risk.
[PMID 18547414] Genotyping panel for assessing response to cancer chemotherapy.
[PMID 19136640] Rapid identification of the hepatic cytochrome P450 2C19 activity using a novel and noninvasive [13C]pantoprazole breath test.
[PMID 21071160] Analysis of 50 SNPs in CYP2D6, CYP2C19, CYP2C9, CYP3A4 and CYP1A2 by MALDI-TOF mass spectrometry in Chinese Han population.
[PMID 21102498] Cytochrome P450 genetic polymorphisms influence the serum concentration of calcineurin inhibitors in allogeneic hematopoietic SCT recipients.
[PMID 21860339] Integration of absorption, distribution, metabolism, and elimination genotyping data into a population pharmacokinetic analysis of nevirapine.
[PMID 22265638] The impact of genetic polymorphisms of P2Y12, CYP3A5 and CYP2C19 on clopidogrel response variability in Iranian patients.
[PMID 22569204] PharmGKB summary: phenytoin pathway.
|qualified_impact||Insufficiently evaluated pharmacogenetic|
|summary||This variant defines the CYP2C19*2 haplotype and is associated with diminished response of clopidogrel (plavix). Compared to individuals who do not have this variant, carriers of this variant are more likely to have a major adverse cardiovascular event despite treatment with clopidogrel.|
[PMID 23517020] Influence of CYP2C19*2 and *3 loss-of-function alleles on pharmacodynamic effects of standard- and high-dose clopidogrel in East Asians undergoing percutaneous coronary intervention: the results of the ACCEL-DOUBLE-2N3 study
[PMID 23661171] CYP2C19 genotypes and their impact on clopidogrel responsiveness in percutaneous coronary intervention
[PMID 24357089] Genetic Polymorphisms of Metabolic Enzymes and the Pharmacokinetics of Indapamide in Taiwanese Subjects
[PMID 24380239] Characterization of the most common CYP2C9 and CYP2C19 allelic variants in the population from the Republic of Macedonia
[PMID 23645039] High prevalence of CYP2C19*2 allele in Roma samples: study on Roma and Hungarian population samples with review of the literature
[PMID 23089684] Similarity in recombination rate and linkage disequilibrium at CYP2C and CYP2D cytochrome P450 gene regions among Europeans indicates signs of selection and no advantage of using tagSNPs in population isolates.
[PMID 23111422] Pharmacogenetics-based population pharmacokinetic analysis of etravirine in HIV-1 infected individuals.
[PMID 23133420] Pharmacogenomic Diversity among Brazilians: Influence of Ancestry, Self-Reported Color, and Geographical Origin.
[PMID 23175667] Increased hospital stay and allograft dysfunction in renal transplant recipients with Cyp2c19 AA variant in SNP rs4244285.
[PMID 24519754] CYP2C19 genotype-phenotype discordance in patients with multiple myeloma leads to an acquired loss of drug-metabolising activity
|Disease||Mephenytoin Proguanil Clopidogrel response|
|CLNDBN||Mephenytoin, poor metabolism of Proguanil, poor metabolism of Clopidogrel response|
|CLNSRC||OMIM Allelic Variant|
|CLNACC||RCV000018393.23, RCV000018394.27, RCV000018395.24,|
[PMID 26021325] The CYP2C19 Intron 2 Branch Point SNP is the Ancestral Polymorphism Contributing to the Poor Metabolizer Phenotype in Livers with CYP2C19*35 and CYP2C19*2 Alleles