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PHARMACOGENOMICS (PGx)

Cardiovascular PGx Test Panel

Cardiovascular PGx Test Panel

CYP2C19, CYP2C9, VKORC1, SLCO1B1, CYP2D6, ADRA2A, CYP3A4, CYP3A5, CYP4F2

Many of cardiovascular medications are metabolized by certain cytochromes in liver. The exact same dose of a medication can produce different results in different individuals. This inter-individual variability can be due to genetic of such cytochromes or other genetic pathways. If someone has increased activity of these cytochromes, the drugs may be eliminated from body more quickly resulting in decreased efficacy. If someone has decreased activity of these cytochromes, the drugs may be built up in body resulting in toxicity. Therefore, determining the genetic make-up of an individual can help with precision prescribing of the medications.

Clopidogrel is a prodrug which needs to be activated by by a cytochrome called CYP2C19. According to American College of Cardiology Foundation/American Heart Association Acute Coronary Syndrome (ACS) guidelines, genetic testing for CYP2C19 loss-of-function alleles should be considered on a case-by-case basis, especially in individuals with recurrent ACS while receiving treatment with clopidogrel.
“Error and trial approach” in case of a life-threatening condition such as acute coronary event especially may not be advisable.

The Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline recommends using an alternative agent in patients with at least one decreased function allele due to risk for decreased response. Patients with genotype of increased metabolism should be monitored for increased bleeding risk

Warfarin, a vitamin K antagonist is a commonly used anticoagulation medication with significant inter-individual variability and narrow therapeutic index leading to frequent complications due to over and under dosing. Genetic variants in CYP2C9, CYP4F2 and vitamin K epoxide reductase complex subunit 1 (VKORC1) can predict the dose needed to meet the therapeutic level.

Statins
Concomitant use of statins such as simvastatin with certain drugs may lead to increased blood concentration of simvastatin resulting in myotoxicity. An alternative agent or a reduced dose of simvastatin should be prescribed to patients with at least one reduced function allele in SLCO1B1.

 

Frequency of Cytochrome P450 (CYP2D6, CYP2C9, CYP2C19) Metabolizer Types in the population

Cytochrome Poor metabolizer Intermediate metabolizer Normal metabolizer Rapid or ultra-rapid metabolizer
CYP2D6 4-7% 9-35% 50-90% 2-3%
CYP2C9 3% 30% 68% N/A
CYP2C19 2-20% 24-36% 14-44% 30%

 

Anticoagulants and Antiplatelet agents (Blood thinners)

Medication Gene
Warfarin* VKORC1, CYP2C9, CYP4F2
Clopidogrel CYP2C19
Ticagrelor CYP3A4, CYP3A53
Prasugrel CYP2C19
Acenocoumarol CYP2C9

*CPIC guideline pharmacogenetic algorithm https://cpicpgx.org/content/guideline/publication/warfarin/2017/28198005.pdf

 

Hyperlipidemia (High blood cholesterol)

Medication Gene
Simvastatin SLCO1B1
Atorvastatin CYP3A4, CYP3A5

 

Hypertension (High blood pressure)

Medication Gene
Beta Blockers (Carvedilol, Timolol, Metoprolol, Propranolol, Nebivolol) CYP2D6
Clonidine ADRA2A

 

Antiarrhythmics (Irregular Heart Rhythm)

Medication Gene
Flecainide CYP2D6
Propafenone CYP2D6

Drug To Drug Interaction

For drug-drug interactions, please go to Flockhart Table ™

References

  • Evans WE, McLeod HL. Pharmacogenomics -- Drug Disposition, Drug Targets, and Side Effect. The New England Journal of Medicine. 2003;348(6):538-549.
  • Johnson, J. A., & Cavallari, L. H. (2013). Pharmacogenetics and Cardiovascular Disease Implications for Personalized Medicine. Pharmacological Reviews, 65(3), 987–1009.
  • Cavallari LH, Lee CR, Beitelshees AL, et al. Multisite Investigation of Outcomes With Implementation of CYP2C19 Genotype-Guided Antiplatelet Therapy After Percutaneous Coronary Intervention. JACC: Cardiovascular Interventions. 2018;11(2):181-191. doi:10.1016/j.jcin.2017.07.022
  • Jneid H, Anderson JL, Wright RS, et al. 2012 ACCF/AHA focused update of the guideline for the management of patients with unstable angina/Non-ST-elevation myocardial infarction (updating the 2007 guideline and replacing the 2011 focused update): a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines. Circulation. 2012;126(7):875-910. doi:10.1161/CIR.0b013e318256f1e0
  • Scott SA, Sangkuhl K, Stein CM, et al. Clinical Pharmacogenetics Implementation Consortium Guidelines for CYP2C19 Genotype and Clopidogrel Therapy: 2013 Update. Clinical Pharmacology & Therapeutics. 2013;94(3):317-323. doi:10.1038/clpt.2013.105
  • Johnson JA, Caudle KE, Gong L, et al. Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for Pharmacogenetics‐Guided Warfarin Dosing: 2017 Update.
  • Study of the Effectiveness of Additional Reductions in C, Homocysteine Collaborative G. Intensive lowering of LDL cholesterol with 80 mg versus 20 mg simvastatin daily in 12 064 survivors of myocardial infarction: a double-blind randomised trial. Lancet, The. 2010;376(9753):1658-1669. doi:10.1016/S0140-6736(10)60310-8
  • The SCG. SLCO1B1 Variants and Statin-Induced Myopathy -- A Genomewide Study. The New England Journal of Medicine. 2008;359(8):789-799. doi:10.1056/NEJMoa0801936
  • https://cpicpgx.org/genes-drugs
  • https://www.fda.gov/drugs/science-and-research-drugs/table-pharmacogenomic-biomarkers-drug-labeling
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