{{Rsnum
|rsid=4244285
|Gene=CYP2C19
|Chromosome=10
|position=94781859
|Orientation=plus
|ReferenceAllele=G
|GMAF=0.1983
|Assembly=GRCh38
|GenomeBuild=38.1
|dbSNPBuild=141
|Summary=Clopidogrel (Plavix®)
|geno1=(A;A)
|geno2=(A;G)
|geno3=(G;G)
|Gene_s=CYP2C19
}}{{CPMC SNP
|link=https://cpmc.coriell.org/Sections/Results/Plavix.aspx?PgId=212
}}{{ population diversity
| geno1=(A;A)
| geno2=(A;G)
| geno3=(G;G)
| CEU | 4.8 | 19.0 | 76.2
| HCB | 0.0 | 51.1 | 48.9
| JPT | 6.8 | 43.2 | 50.0
| YRI | 3.2 | 21.0 | 75.8
| ASW | 0.0 | 0.0 | 0.0
| CHB | 0.0 | 51.1 | 48.9
| CHD | 0.0 | 0.0 | 0.0
| GIH | 0.0 | 0.0 | 0.0
| LWK | 0.0 | 0.0 | 0.0
| MEX | 0.0 | 0.0 | 0.0
| MKK | 0.0 | 0.0 | 0.0
| TSI | 0.0 | 0.0 | 0.0
| HapMapRevision=28
}}
[[rs4244285]] is a SNP in the [[CYP2C19]] gene, potentially encoding the CYP2C19*2 variant. This variant is the most common reason for poor metabolism of compounds like mephenytoin (an anti-convulsant), some antidepressants, the anti-platelet drug [[Plavix]], and some drugs used for [[ulcer]] conditions of various types. {{PMID|8195181}}

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.[http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm204253.htma]

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|OA=1
}}

{{omim
|desc=MEPHENYTOIN, POOR METABOLISM OF
|id=124020
|quiet=1
|rsnum=4244285
|variant=0001
}}

{{PharmGKB
|RSID=rs4244285
|Name_s=CYP2C19*2
|Gene_s=CYP2C19
|Feature=Exon/Syn
|Evidence=PubMed ID:20351750
|Annotation=Risk or phenotype-associated allele: A. Phenotype: A meta-analysis associated CYP2C19*2 with increased risk of major cardiovascular events and stent thrombosis in patients with coronary artery disease receiving clopidogrel. Study size: 8043 (events), 4975 (stent thrombosis). Study population/ethnicity: Patients (mostly European) enrolled in studies of clopidogrel for acute coronary syndromes or stable coronary artery disease. Significance metric(s): RR = 1.96, CI = 1.14-3.37, p = 0.02 (events); RR = 3.82, CI = 2.23-6.54, p = 0.0001 (stent thrombosis). Type of association: CO.
|Drugs=clopidogrel
|Drug Classes=
|Diseases=Angina, Unstable; Cardiovascular Diseases; Ischemia; Myocardial Infarction; Recurrence; Stroke; Thrombosis
|Curation Level=Curated
|PharmGKB Accession ID=PA165349811
}}

{{PharmGKB
|RSID=rs4244285
|Name_s=CYP2C19:681G>A
|Gene_s=CYP2C19
|Feature=Exon/Syn
|Evidence=Web Resource:http://www.pharmgkb.org/search/annotatedGene/cyp2c19/haplotype.jsp#ImportantHaplotypeInformationforCYP2C19-2; Web Resource:http://www.pharmgkb.org/search/annotatedGene/cyp2c19/variant.jsp#ImportantVariantInformationforCYP2C19-681
|Annotation=Introduces a splicing defect resulting in a truncated, non-functional protein responsible for the poor metabolizer phenotype; defining variant for CYP2C19*2.
|Drugs=
|Drug Classes=
|Diseases=
|Curation Level=In-Depth
|PharmGKB Accession ID=PA161145197
}}

{{PharmGKB
|RSID=rs4244285
|Name_s=CYP2C19*2, CYP2C19:G681A
|Gene_s=CYP2C19
|Feature=Exon/Syn
|Evidence=PubMed ID:19106084
|Annotation=Subjects with acute coronary syndromes receiving treatment with clopidogrel and who carried two copies of CYP2C19 loss-of-function/reduced function alleles (two copies of CYP2C19*2; or one copy of CYP2C19*2 and one copy of CYP2C19*3, CYP2C19*4 or CYP2C19*8) had a relative increase of 53% in risk of death from cardiovascular causes, myocardial infarction, or stroke, as compared with noncarriers. Subjects were participants in the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial Infarction (TRITON-TIMTI) 38. 97.6% of the study participants were Caucasian. In a separate cohort of healthy subjects treated with clopidogrel, carriers of at least one reduced-function CYP2C19 allele had significantly lower levels of clopidogrel's active metabolite and diminished platelet inhibition.
|Drugs=clopidogrel
|Drug Classes=
|Diseases=Cardiovascular Diseases; Death; Myocardial Infarction; Stroke
|Curation Level=Curated
|PharmGKB Accession ID=PA162363763
}}

{{PharmGKB
|RSID=rs4244285
|Name_s=CYP2C19*2, CYP2C19:G681A
|Gene_s=CYP2C19
|Feature=Exon/Syn
|Evidence=PubMed ID:19106083
|Annotation=Subjects who had previously experienced myocardial infarction and were receiving clopidogrel were almost twice as likely to experience a subsequent cardiovascular event if they carried any two CYP2C19 loss-of-function alleles (CYP2C19*2, CYP2C19*3, CYP2C19*4 or CYP2C19*5) relative to those with none. Patients from this study who underwent percutaneous coronary intervention and carried two CYP2C19 loss-of-function alleles had a 3.58 times greater risk of cardiovascular events as those with none. These results suggest that treatment with clopidogrel is less effective in individuals who are homozygous for CYP2C19 loss-of-function alleles than in those who do not carry CYP2C19 loss-of-function alleles.
|Drugs=clopidogrel
|Drug Classes=
|Diseases=Cardiovascular Diseases; Death; Myocardial Infarction; Stroke
|Curation Level=Curated
|PharmGKB Accession ID=PA162363760
}}

{{PharmGKB
|RSID=rs4244285
|Name_s=CYP2C19*2
|Gene_s=CYP2C19
|Feature=Exon/Syn
|Evidence=PubMed ID:16338278
|Annotation=In contrast to other PPIs, esomeprazole-induced healing of GERD appears to be unrelated to the CYP2C19*2 variant.
|Drugs=esomeprazole
|Drug Classes=
|Diseases=Gastroesophageal Reflux
|Curation Level=Curated
|PharmGKB Accession ID=PA162652696
}}

{{PharmGKB
|RSID=rs4244285
|Name_s=CYP2C19*2; CYP2C19:681G>A
|Gene_s=CYP2C19
|Feature=Exon/Syn
|Evidence=PubMed ID:19706858
|Annotation=This loss-of-function variant CYP2C19*2 was associated with diminished platelet response to clopidogrel treatment and poorer cardiovascular outcomes.
|Drugs=clopidogrel
|Drug Classes=
|Diseases=Cardiovascular Diseases
|Curation Level=In-Depth
|PharmGKB Accession ID=PA165106755
}}

{{PharmGKB
|RSID=rs4244285
|Name_s=CYP2C19*2 (G>A)
|Gene_s=CYP2C19
|Feature=Exon/Syn
|Evidence=PubMed ID:20147896
|Annotation=Risk or phenotype-associated allele: A allele. Phenotype: Increased omeprazole levels given ritonavir/tipranavir. Study size: 23 (7 female). Study population/ethnicity: 16 Caucasians, 7 African American. Significance metric(s): P = 0.0026. Type of association: GN; PK.
|Drugs=omeprazole; ritonavir; tipranavir
|Drug Classes=
|Diseases=
|Curation Level=Curated
|PharmGKB Accession ID=PA165291907
}}
{{PMID Auto
|PMID=21247447
|Title=CYP2C19 and ABCB1 gene polymorphisms are differently distributed according to ethnicity in the Brazilian general population
|OA=1
}}

{{PMID Auto
|PMID=17048007
|Title=Association of warfarin dose with genes involved in its action and metabolism.
|OA=1
}}

{{PMID Auto
|PMID=18521743
|Title=CYP2C19*17 is associated with decreased breast cancer risk.
}}

{{PMID Auto
|PMID=18547414
|Title=Genotyping panel for assessing response to cancer chemotherapy.
|OA=1
}}

{{PMID Auto
|PMID=19136640
|Title=Rapid identification of the hepatic cytochrome P450 2C19 activity using a novel and noninvasive [13C]pantoprazole breath test.
|OA=1
}}

{{PMID Auto
|PMID=21071160
|Title=Analysis of 50 SNPs in CYP2D6, CYP2C19, CYP2C9, CYP3A4 and CYP1A2 by MALDI-TOF mass spectrometry in Chinese Han population.
}}

{{PMID Auto
|PMID=21102498
|Title=Cytochrome P450 genetic polymorphisms influence the serum concentration of calcineurin inhibitors in allogeneic hematopoietic SCT recipients.
}}

{{PMID Auto
|PMID=21860339
|Title=Integration of absorption, distribution, metabolism, and elimination genotyping data into a population pharmacokinetic analysis of nevirapine.
}}

{{PMID Auto
|PMID=22265638
|Title=The impact of genetic polymorphisms of P2Y12, CYP3A5 and CYP2C19 on clopidogrel response variability in Iranian patients.
}}

{{PMID Auto
|PMID=22569204
|Title=PharmGKB summary: phenytoin pathway.
|OA=1
}}

{{GET Evidence
|impact=pharmacogenetic
|qualified_impact=Insufficiently evaluated pharmacogenetic
|inheritance=dominant
|quality_scores=Array
|dbsnp_id=rs4244285
|overall_frequency_n=1660
|overall_frequency_d=10752
|overall_frequency=0.15439
|n_genomes=13
|n_genomes_annotated=0
|n_haplomes=15
|n_articles=5
|n_articles_annotated=5
|qualityscore_in_silico=3
|qualitycomment_in_silico=Y
|qualityscore_in_vitro=2
|qualitycomment_in_vitro=Y
|qualityscore_case_control=4
|qualitycomment_case_control=Y
|qualityscore_severity=5
|qualitycomment_severity=Y
|qualityscore_treatability=4
|qualitycomment_treatability=Y
|in_pharmgkb=Y
|autoscore=1
|webscore=N
|summary_short=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.
}}

[[Clopidogrel Efficacy]]

{{PMID Auto
|PMID=23517020
|Title=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 Auto
|PMID=23661171
|Title=CYP2C19 genotypes and their impact on clopidogrel responsiveness in percutaneous coronary intervention
}}

{{PMID Auto
|PMID=24357089
|Title=Genetic Polymorphisms of Metabolic Enzymes and the Pharmacokinetics of Indapamide in Taiwanese Subjects
}}

{{PMID Auto
|PMID=24380239
|Title=Characterization of the most common CYP2C9 and CYP2C19 allelic variants in the population from the Republic of Macedonia
}}

{{PMID Auto
|PMID=23645039
|Title=High prevalence of CYP2C19*2 allele in Roma samples: study on Roma and Hungarian population samples with review of the literature
}}

{{PMID Auto
|PMID=23089684
|Title=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 Auto
|PMID=23111422
|Title=Pharmacogenetics-based population pharmacokinetic analysis of etravirine in HIV-1 infected individuals.
}}

{{PMID Auto
|PMID=23133420
|Title=Pharmacogenomic Diversity among Brazilians: Influence of Ancestry, Self-Reported Color, and Geographical Origin.
|OA=1
}}

{{PMID Auto
|PMID=23175667
|Title=Increased hospital stay and allograft dysfunction in renal transplant recipients with Cyp2c19 AA variant in SNP rs4244285.
}}

{{PMID Auto
|PMID=24519754
|Title=CYP2C19 genotype-phenotype discordance in patients with multiple myeloma leads to an acquired loss of drug-metabolising activity
}}
{{on chip | 23andMe v2}}
{{on chip | 23andMe v3}}
{{on chip | 23andMe v4}}
{{on chip | FTDNA2}}
{{on chip | HumanOmni1Quad}}