Cardiology

Cardiology medications like anticoagulation and antiplatelet drugs are among the most frequently prescribed medications in the United States. These medications are known to have very narrow therapeutic windows and high variability in patient responses. Seemingly similar cardiology patients can sometimes require as much as a 10-20x difference in dosage depending on their diagnosis, medication selection, and genetics (3). 

Medical Necessity for Pharmacogenetic Testing in Cardiology Patients

The FDA now has pharmacogenetic testing recommendations on several common cardiology drug warning labels such as Clopidogrel and Warfarin. Pharmacogenetics testing is deemed a "medically necessity" prior to the initiation of Plavix/ Clopidogrel in Acute Coronary Syndrome patients undergoing percutaneous coronary intervention (3). The severity of adverse drug reactions associated with cardiology drugs dictates a critical need for pharmacogenetics testing of all patients that meet PRIMER selection criteria guidelines. Our PRIMER panel is the most inclusive, most relevant genomic assay currently available to cardiology health care professionals!

Common Cardiology Medication Metabolism Pathways

Copyright PGXL Laboratories 2016

"Normal Metabolizers": How Normal Is Normal?

Copyright PGXL Laboratories 2016

Cardiology Relevant Genes In The PRIMER Panel

Gene - Gene Product Description

CYP2D6 – Metabolizes more than 25% of all drugs, including tamoxifen, many antidepressants, antipsychotics, beta-blockers, and opioids.  Detecting variants of the CYP2D6 gene that cause altered enzymatic activity can identify patients who may be at increased risk of having adverse drug reactions or therapeutic failure to standard dosages of CYP2D6 substrates.  Medications which require activation or inactivation by CYP2D6 should be used with caution in patients with CYP2D6 variants.

CYP2C19 – Metabolizes approximately 10-15% of all drugs, including clopidogrel, citalopram, diazepam, and many of the proton pump inhibitors.  Detecting variants of the CYP2C19 gene that cause altered enzymatic activity can identify patients who may be at increased risk of having adverse drug reactions or therapeutic failure to standard dosages of CYP2C19 substrates.

CYP2C9 – Metabolizes approximately 10% of all drugs, including warfarin, phenytoin, non-steroidal anti-inflammatory drugs (NSAIDs), and antihyperglycemic sulphonylureas.  Detecting variants of the CYP2C9 gene that cause altered enzymatic activity can identify patients who may be at increased risk of having adverse drug reactions or therapeutic failure to standard dosages of CYP2C9 substrates.

CYP3A4 - A liver enzyme that, in concert with CYP3A5, metabolizes approximately 50% of medications, including many of the statins, benzodiazepines, antibiotics, and antipsychotics. Detecting variants of the CYP3A4 gene that cause altered enzymatic activity can identify patients who may be at increased risk of having adverse drug reactions while taking standard dosages of 3A4 substrates. Roughly 4-10% of the general population possesses inherited differences in 3A4 that cause decreased metabolism. These Decreased Metabolizers may be at increased risk for dose-dependent side effects to drugs normally inactivated by 3A4.

 

CYP3A5 – A liver enzyme that, in concert with CYP3A4, metabolizes approximately 50% of medications, including many of the statins, benzodiazepines, antibiotics, and antipsychotics. Detecting variants of the CYP3A5 gene that cause altered enzymatic activity can identify patients who may be at increased risk of having adverse drug reactions while taking standard dosages of 3A5 substrates. More than half of the general population (60-80%) possesses inherited differences in 3A5 that cause decreased metabolism. These Decreased Metabolizers may be at increased risk for dose-dependent side effects to drugs normally inactivated by 3A5.

CYP1A2 – Metabolizes many medications, including theophylline, diazepam, caffeine, and amitriptyline.  CYP1A2 can be induced by several medications, substrates, and constituents of tobacco smoke.  CYP1A2 can also be inhibited by several medications.  Basal metabolic capacity remains relatively consistent among the different genotypes in the absence of an inducer.  Detecting variants of the CYP1A2 gene that cause altered enzymatic induction in the presence of an inducer can identify patients who may be at increased risk of having adverse drug reactions or therapeutic failure to standard dosages of CYP1A2 substrates.

VKORC1 – Warfarin is the most commonly prescribed anticoagulant for the treatment and prevention of thromboembolic events. The anticoagulant effect of warfarin is due to the inhibition of Vitamin K epoxide reductase enzyme, leading to a reduction of the Vitamin K pool and an inability to activate the Vitamin K dependant clotting factors. The active component of warfarin is metabolized by Cytochrome P450 2C9 (CYP2C9). Polymorphisms in the CYP2C9 gene are associated with decreased warfarin clearance and an increased risk of bleeding. An additional polymorphism in the Vitamin K reductase complex subunit 1 (VKORC1) gene is also associated with warfarin sensitivity and decreased maintenance dose requirements of the medication. By testing for the inherited differences in VKORC1 and CYP2C9, and taking into considerations patient physical characteristics our lab partners can estimate individual warfarin daily maintenance doses and subsequently identify those patients who will require low doses. Thus, the potential for bleeding events and other Adverse Drug Reactions can be reduced. 

SLCO1B1 – This gene encodes the liver enzyme OATP1B1, which assists in transport of statins medications into the liver. Roughly 15% of the population possess the *5 variant, an inherited form of SLOC1B1 which increases risk of statin-induced myopathy 3 to 5 fold. Risk of myopathy with the *5 variant is most closely associated with simvastatin and to a lesser extent, atorvastatin. Patients with the *5 variant may need the lowest doses of simvastatin or an alternative statin to reduce risk of myopathy. 

MTHFR – The MTHFR (Methylenetetrahydrofolate Reductase) enzyme catalyzes the formation of 5-methyltetrahydrofolate, the major circulating form of active folate.  Absence of active folate leads to accumulation of plasma homocysteine.  The 677 C>T polymorphism of MTHFR leads to decreased MTHFR enzymatic activity and elevated homocysteine.  The 1298 A>C polymorphism is associated with significant increases plasma homocysteine levels only when in combination with the 677 C>T polymorphism.   Elevated plasma homocysteine has been shown to be a risk factor for atherosclerotic heart disease, myocardial infarction, cerebrovascular disease, and venous thrombosis.  Additionally, associations between the 677 C>T polymorphism and increased risk for methotrexate toxicity, increased chemosensitivity of colon and breast cancers to 5-fluorouracil, and increased risk of fetal neural tube defects in pregnant women have also been reported, although these associations remain controversial.

Factor 2 – The Factor II (prothrombin) polymorphism is the result of a single point mutation (20210 G>A) in the 3’ untranslated region of the gene. The 20210 G>A gives rise to increased circulating prothrombin levels, thus creating the potential of a hypercoagulable state. This polymorphism is found in approximately 2% of individuals in the U.S. and it raises the risk of thrombosis significantly for both males and females in all age groups. People with this polymorphism are at 2-3 fold increased risk of deep venous thrombosis (DVT), without other confounding non-genetic factors such as smoking, hormone therapy, and immobility.

Factor 5 - The Factor V Leiden polymorphism is the result of a single point mutation (1691 G>A) that results in substitution of a glutamine for arginine at amino acid 506. The amino acid change prohibits the inactivation of Factor V by activated protein C, thereby creating a state of activated protein C resistance (APCR) and increasing the risk of thrombosis. Individuals with this polymorphism have a 10-20 fold increased thrombotic risk.

References 

1) Menu of Tests [Internet]Louisville, KY: PGXL Laboratories; c2016 [cited 2016 11/20]. Available from: http://www.pgxlab.com/test-menu/.

2) Pathways for common medications. Louisville, KY: PGXL Laboratories; 2016:PGXL Primer. Personalized Medicine. Results For Life.

3) Reynolds et al Pers Med 2007; Zhu et al Clin Chem 2006; Linder et al J Thrombosis Thrombolysis 2002.

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