Your Code for Personalized Medicine

 

Molecular analysis reveals a patient’s unique genetic ‘signature’ or expression.

Molecular Diagnostics in Cardiology

Genetic testing (molecular diagnostics and pharmacogenomics) makes it possible to know a priori how your cardiac patients will metabolize a specific drug. Approximately 75% of the population has genetic variations that can increase or decrease the availability of cytochrome enzymes that are essential for proper drug metabolism and conversion. The comprehensive genetics4you™ MDx cardiac panel assesses 5 CYP enzymes— 2C19, 2C9, 2D6, 3A4 and 3A5, as well as 3 genes with well documented variants—Factor II, Factor V Leiden and Mthfr, which are useful to identify inherited risk factors related to prothrombin deficiency, hyperhomocysteinemia and thrombosis.

Pharmacogenomic Testing

Clinical studies have reported that about 30% of patients treated with clopidogrel (Plavix) using standard doses respond poorly, thus increasing their risk of a catastrophic cardiovascular event.(1,3) Warfarin has a very narrow therapeutic range making dosing extremely critical.(9,10) Factor II, Factor V Leiden and Mthfr variants can help identify patients at increased risk for venous thrombosis, bleeding or strokes.7

Genetic testing benefits the doctor, the patient—and the heathcare system by delivering better outcomes and potential savings by treating patients with the right drug the first time and by reducing the number of potentially serious adverse reactions.

 genetics4you™ 

Molecular Diagnostic (MDx) Cardiac Assays :  General Overview

This comprehensive cardiac genotyping panel consists of a total of eight genetics4you™ molecular diagnostic assays that help identify the primary inherited genetic and pharmacogenomic biomarkers that determine individual metabolic compatibility with clopidogrel (Plavix), warfarin (Coumadin), ticragrelor (Brilinta) and beta blockers (propranolol i.e. Inderal) and the level of risk associated with Type III venous thrombosis, hyperlipoproteinemia, and inherited thrombophilia.

• CYP450 2C19 Clopidogrel (Plavix)

• CYP450 2C9/VKORC1 Warfarin Resistance (Coumadin)

• CYP450 2D6 Beta Blocker Resistance (Propranolol / Inderal)

• CYP450 3A4/3A5 Protease Inhibitors (Statins / Calcium Channel Blockers)

• Factor II Prothrombin Deficiency

• Factor V Leiden Inherited Thrombophilia

• MTHFR Hyperhomocysteinemia

FDA Updates PLAVIX Package Insert with Black  Box Warning2

The warning addresses patients that do not effectively metabolize clopidogrel (i.e. poor metabolizers) who will not be able to effectively convert Plavix into its active form, and as such, will not receive the full benefits of the anticoagulant. The FDA informs healthcare providers of the existence of tests (molecular diagnostics) that can identify the genetic differences in patients’ CYP2C19 metabolic function.2 Medicare, Medicaid and many major carriers reimburse for these tests. Approximately 120 drugs now have similar labeling since many drugs are metabolized via the cytochrome P450 pathway.

A physician reviews the molecular diagnostic cardiac panel genotyping results with a patient and prescribes a ’tailored’ treatment plan based on their unique ‘genetic signature’.

 genetics4you™ 

Molecular Diagnostics for Cardiology : Detailed Description

 

[CYP450 2C19 Genotyping Test]

Clinical Relevance: Approximately 25% of all outpatient prescription drugs filled in the US are taken by patients with genetic polymorphisms that affect absorption, metabolism or excretion.4 CYP2C19 metabolizes ~15% of all drugs. Plavix (clopidogrel) is the world’s second best selling drug. Genetic variation that impairs metabolism is seen in 30% of Caucasians, 40% of African Americans and 55% of East Asians.3 Studies indicate that carriers of a reduced function allele for CYP2C19 have a 3.58X greater risk for major adverse CV events and a 53% relative higher risk of death over 15 months due to CV causes, MI or stroke. Stent patients have a threefold increased risk of stent thrombosis.3

Genetic Variants: CYP450 2C19 *2, *3, *4, *5, *6, *7, *8, *9, *10, *13 and *17 alleles. 

 

[CYP450 2C9/VKORC1 Genotyping Test]

Clinical Relevance: Warfarin is the most widely pre­scribed anticoagulant for the prevention and treatment of thromboembolic events. The active metabolizer of warfarin is CYP2C9. Other polymorphisms in the CYP2C9 gene are associated with decreased warfarin clearance and increased risk of bleeding. Major bleeding occurred during the first 90 days after treatment in 50% of patients.5 Another polymorphism is the VKORC1 gene which is associated with warfarin sensitivity and decreased maintenance dose requirements of the medication. Complications of warfarin therapy account for over 10% of hospital admissions and 15% of all severe drug-induced adverse events. Studies indicate that routine incorporation of genetic testing into warfarin therapy protocols significantly ease both the health and financial risks currently associated with treatment.

Genetic Variants: CYP450 2C9 *2, *3 and VKORC1 3673(-1639G>A) alleles.

 

[CYP450 2D6 Genotyping Test]

Clinical Relevance: CYP2D6 metabolizes more than 25% of all drugs, including tamoxifen, many antidepressants, antipsychotics, beta-blockers and opioids. This assay detects variants of the CYP2D6 gene in patients that cause altered enzymatic activity that increase the risk of adverse drug reactions or therapeutic failure to standard dosages of CYP2D6 substrates. Medications requiring activation or inactivation by CYP2D6 should be used with caution in patients with these variants. Patients are categorized as extensive metabolizers (EM), intermediate metabolizers (IM), poor metabolizers (PM) or ultra-extensive metabolizers (UM). Indicated for use in determining strategy and treatment doses for therapeutics that are metabolized by the CYPY2D6 gene product. If coadministered with a CYP2D6 inhibitor, blood levels and effect of the beta blocker may increase resulting in bradycardia, hypotension or heart failure with the highest risk in extensive metabolizers (EM).6

Genetic Variants: *2, *3, *4, *5, *6, *7, *8, *9, *10, *11, *12, *14, *15, *17 and *41.

 

[CYP450 3A4/3A5 Genotyping Test]

Clinical Relevance: CYP3A4 and 3A5 metabolize up to 50% of all clinical drugs, including statins, calcium chan­nel blockers, benzodiazepines, antipsychotics, opioids, antidepressants, acetaminophen and chemotherapeutics. The FDA recommends 3A4/3A5 genetic testing prior to initiating or reinitiating treatment with Ticragrelor (Brilinta) or Fluvoxamine. 3A4/3A5 metabolic abnormalities exist in ~1 of 100 patients.

Genetic Variants: CYP450 3A4 *1B, *2, *3, *12 and *17 andCYP450 3A5 *1D, *2, *3, *3B, *6, *7, *8 and *9 alleles.

 

[Factor II/V/MTHFR Genotyping Test]

Clinical Relevance: The Factor V Leiden mutation is the most common variant associated with inherited thrombosis. Its prevalence is ~4-6% in the general US population, and accounts for 85-95% of activated protein C resistant cases.7 The Factor II (Prothrombin variant gene is the sec­ond most common genetic defect for inherited thrombosis and is present in 1-2% of the general population.(7, 8) Hyper­homocysteinemia is a risk factor for coronary artery disease, venous thrombosis and stroke. Methlyenetetrahydrofolate reductase (MTHFR) is a key enzyme in the metabolism of homocysteine.

Genetic Variants: FV G1691A, FII G20210A, MTHFR A1298C and C677T alleles.

 

CLINICAL REFERENCES