COMPREHENSIVE PERSONALIZED MEDICINE PANEL
The Alpha Genomix Comprehensive Personalized Medicine Report is an all-inclusive report providing patient-specific, evidence-based information covering key genes implicated in pharmacogenetics. This report delivers dosing guidance for currently affected medications, additional risk factors and a listing of all potentially risk-related medications to assist clinicians in determining the most effective dose and medication well into the future.
The CYP1A2 is involved in the metabolism of 8-10% of commonly used drugs as well as natural compounds such as caffeine. A large number of CYP1A2 variants have been identified and have been shown to influence an individual’s ability to metabolize drugs including clozapine (Clozaril), duloxetine (Cymbalta), and olanzapine (Zyprexa). The CYP1A2 assay identifies some common variants associated with variability in CYP1A2 enzyme activity.
The CYP2B6 is responsible for the metabolism of 4% of the top 200 prescribed drugs, such as cyclophosphamide and bupropion (Wellbutrin). A large number of variants have been reported. The CYP2B6 assay identifies some common variants associated with variability in CYP2B6 enzyme activity
The CYP2C8 is responsible for the metabolism of 5% of currently used drugs that undergo phase I hepatic metabolism such as rosiglitazone (Avandia), pioglitazone (Actos), repaglinide (Prandin), paclitaxel, Cerivastatin (withdrawn from the market worldwide in 2001, due to reports of fatal rhabdomyolysis.), Amodiaquine (this is used for malaria – doesn’t show up on LexiComp – my drug resource) and NSAIDs. To date different variants of CYP2C8 have been identified. The CYP2C8 assay identifies some common variants associated with variability in CYP2C8 enzyme activity.
The CYP2C9 is involved in the metabolism of 15% of clinically important medications such as fluoxetine (Prozac), phenytoin (Dilantin), primidone (Mysoline), celecoxib (Celebrex), diclofenac (Voltaren), sulindac (Clinoril), naproxen (Aleve), and warfarin (Coumadin). To date 30 different variants of CYP2C9 have been identified. The CYP2C9 assay identifies some common variants associated with variability in CYP2C9 enzyme activity.
The CYP2D6 is involved in the metabolism of 25% of clinically important medications such as desipramine (Norpramin), duloxetine (Cymbalta), hydrocodone (Norco), venlafaxine (Effexor), atomoxetine (Strattera), metoprolol (Lopressor), carvedilol (Coreg), flecainide (Tambocor), and buprenorphine (Butrans). To date more than a 100 different variants have been identified. The CYP2D6 assay identifies common variants associated with variability in CYP2D6 enzyme activity.
CYP3A4 and 3A5 are involved in the metabolism of approximately 50% of commonly used drugs such as fentanyl (Duragesic), alprazolam (Xanax), zolpidem (Ambien), atorvastatin (Lipitor), clopidogrel (Plavix), losartan (Cozaar), and apixaban (Eliquis). CYP3A4 and CYP3A5 enzymes have overlapping substrate specificity and the contribution of CYP3A5 in the overall metabolism is smaller than the one for CYP3A4. The overall CYP3A metabolism status is expected to affect drugs that have narrow therapeutic index. The CYP3A assay tests for the presence of CYP3A genetic variants that can influence its activity.
Alpha-2-adrenergic receptor 2 A (ADRA2A) is a G protein-coupled receptor that has a critical role in regulating neurotransmitter release from sympathetic nerves and from adrenergic neurons in the central nervous system. A number of variants of the ADRA2A gene have been reported to have varied responses to certain drugs. Pediatric patients with the CC genotype and attention deficit hyperactivity disorder (ADHD) may have a poorer response to methylphenidate treatment as compared to pediatric patients with the CG or GG genotype. Other genetic and clinical factors may also influence response to methylphenidate.
Apolipoproteins (APO) are structural constituents of lipoprotein particles that play critical roles in blood lipid metabolism and transport. Apolipoprotein E (APOE) is a major constituent of triglyceride-rich chylomicrons, very low-density lipoproteins (VLDL) and some subclasses of high-density lipoprotein (HDL). Defects in APOE can result in dyslipidemia, which is an important risk factor in the genesis of atherosclerosis and subsequent development of cardiovascular disease. The APOE assay tests for APOE mutations that predict risks for cardiovascular disease.
Catechol-O-Methyltransferase (COMT) is an enzyme responsible for the metabolism of catecholamines and catechol-estrogens in both the central nervous system and other organs. Dopamine is cleared mainly by COMT in the frontal cortex and a reduced activity of this enzyme results in higher synaptic levels of dopamine, which affects prefrontal cortex cognitive response to certain drugs. A single nucleotide polymorphism of the COMT gene produces an amino acid change from Valine to Methioinine (Val158Met) and reduces enzyme activity by 3 to 4 folds. The COMT assay tests for mutations associated with decreased activity of COMT.
DRD2 and ANKK1 are closely linked genes that encode the D2 subtype of the Dopamine Receptor (DRD2). DRD2 is a G protein-coupled receptor located within the brain. Variant allele DRD2:Taq1A has been associated with a reduced number of dopamine binding sites which may play a role in increased addictive behavior, nicotine dependence, and increased motor fluctuations in patients with Parkinson’s disease. The DRD2/ANKK1 assay tests for the presence of the DRD2:Taq1A gene.
Clotting Factor II, or prothrombin, is a Vitamin K-dependent pro-enzyme that functions in the blood coagulation cascade. It is a precursor to thrombin, which in turn strengthens a protective clot. The prothrombin 20210G>A mutation in the Factor II gene, results in increased levels of plasma prothrombin and a concurrent increased risk for thrombosis. Prothrombin-related thrombophilia is characterized by venous thromboembolism (VTE). The Factor II assay tests for the presence of mutations associated with increased risk for thrombosis.
Factor V Leiden
The Factor V Leiden gene encodes the coagulation factor V. In normal conditions, Factor V is inactivated during the clotting process by the activated protein (APC). In subjects with factor V Leiden thrombophilia, a mutation produces a Factor V that cannot be inactivated normally by APC and as a result, the clotting process remains active longer than usual leading to more thrombin generation. In the US, the frequency of the factor V Leiden mutation varies by ethnicity with about 5% of Caucasians, 2% of Hispanics, 1% of African Americans. The Factor V Leiden assay tests for the presence of the mutation in the Factor Leiden gene associated with increased risk for thromboembolism.
DPYD is the initial and rate limiting enzyme in the three step pathway of uracil and thymidine catabolism and the pathway leading to the formation of beta-alanine. The DPYD protein is responsible for degrading Fluoropyrimidines, such as 5-fluorouracil (5FU), capecitabine, and tegafur. Decreased DPYD activity is associated with a greater than four-fold risk of severe or fatal toxicity from standard doses of 5FU. The DPYD assay tests for the presence of DPYD mutations associated with decreased DPYD activity.
Glucose-6-Phosphate Dehydrogenase (G6PD) is found in virtually every type of cell where it plays a role in the body’s conversion of sugar to energy. Within red blood cells G6PD provides the primary source of protection against reactive oxygen species. Without this protection a toxic build-up of reactive oxygen species can cause abnormal and excessive red blood cell destruction (hemolysis). Variations in the G6PD gene are associated with G6PD enzyme deficiencies and a higher risk of hemolysis. The G6PD assay tests for variant genes associated with decreased activity of G6PD.
Methylenetetrahydrofolate reductase (MTHFR) is involved in folate metabolism and is essential for the remethylation of homocysteine. Two mutations in the MTHFR gene result in decreased enzyme activity, which is linked to increased plasma homocysteine levels. Mild to moderate hyperhomocysteinemia has been identified as a risk factor for venous thromboembolism and other cardiovascular diseases such as coronary heart disease and stroke. The MTHFR assay tests for mutations in MTHFR gene associated with decreased enzymatic activity of MTHFR.
The mu-opioid receptor (OPRM1) is the primary binding site for many opioid drugs and for binding of beta-endorphins. A number of gene variations have been identified that can influence opioid drugs binding to OPRM1. Patients with the AA genotype who are treated with naloxone (Evzio) may have lower cortisol response as compared to patients with the AG or GG genotype. Other genetic and clinical factors may also influence the response to naloxone.
The SLC6A4 gene encodes the serotonin transporter which is a membrane-spanning protein that regulates synaptic concentrations of serotonin via clearance and reuptake of the neurotransmitter into nerve cells. Serotonin is available to activate receptors only when located in the synaptic space between neurons. The serotonin transporter is the specific target for antidepressants in the Selective Serotonin Reuptake Inhibitor (SSRI) class (e.g. fluoxetine (Prozac), paroxetine (Paxil)) and many of the Tricyclic Antidepressants (e.g. amitriptyline). Variations in the SLC6A4 gene alter the expression of serotonin transporters: influencing response to certain antidepressant medications. The SLC6A4 assay tests for the presence of SLC6A4 variants associated with low functioning protein.
The SLCO1B1 gene encodes a liver-specific transporter involved in the removal of endogenous compounds such as bile acids and bilirubin as well as drugs such as statins from the blood to the liver. Some variants of the SLCO1B1 gene result in a low functioning protein, which impairs statin clearance and may lead to increased risk for muscle pain, tenderness or weakness, associated with myopathy. The SLCO1B1 assay tests for the presence of SLCO1B1 variants associated with low functioning protein.
Sulfotransferase 4A1 is an enzyme encoded by the SULT4A1 gene that functions in the brain to metabolize endogenous compounds such as neurotransmitters. The SULT4A1-1(+) gene has been associated with improved response to atypical antipsychotics such as olanzapine (Zyprexa). Evidence for improved response includes increased remission rates, reduced hospitalizations, and a significant reduction in weight gain compared to carriers of the SULT4A1-1(-) gene. The SULT4A1 assay tests for the presence of SULT4A1 variants that may help guide choice of antipsychotic treatment for patients with psychosis, schizophrenia, or schizoaffective disorder.
Thiopurine S-methyltransferase (TPMT) catalyzes the S-methylation of Thiopurine drugs such as mercaptopurine (Purinethol), and azathioprine (Imuran) as well as other aromatic and heterocyclic sulfhydryl compounds. Genetic variations have been identified and were shown to influence that activity of TPMT enzymatic activity and accordingly it was shown that 88.6% of people had high enzyme activity, 11.1% had intermediate activity, and 0.3% had undetectable activity. The TPMT assay tests for the presence of TMPT variation influence the enzyme’s activity.
The main functions of Uridine Diphosphate Glucuronosyl Transferase 1A1 (UGT1A1) lie within the liver, where it is the sole enzyme responsible for the metabolism of Bilirubin, the hydrophobic breakdown product of heme catabolism. In addition, UGT1A1 is involved in the metabolism of cancer drugs such as etoposide (Toposar), irinotecan (Camptosar) and raloxifene (Evista). UGT1A1 is inhibited by drugs such as atazanavir (Reyataz), indinavir (Crixivan) and tranilast (Rizaben) (tranilast (Rizaben) is not available in the United States). To date, 113 different UGT1A1 variants have been described. These variants can confer reduced or increased activities, as well as inactive or normal enzymatic activity. The UGT1A1 assay tests for variants that can influence the enzymatic activity of UGT1A1.
The UGT2B15 enzymes are of major importance in the elimination of potentially toxic compounds. It has been implicated in the metabolism of oxazepam and various gene variants have shown differential response to this drug. Patients with the AA genotype who are treated with oxazepam may have a decreased oxazepam oral clearance as compared to patients with the CC genotype, which the study reports resulted in no differences in pharmacodynamic measures. Other genetic and clinical factors may also influence the oral clearance of oxazepam. Patients with the AC genotype who are treated with oxazepam may have a decreased oxazepam oral clearance as compared to subjects with the CC genotype. The UGT2B15 assay tests for variants that can influence the enzymatic activity of UGT2B15.
Vitamin K Epoxide Reductase Complex, subunit 1 (VKORC1) is the target of anticoagulants. Mutations in the VKORC1 gene results in altered sensitivities towards anticoagulants. VKORC1 genotype defines three levels of clinical phenotypes, high sensitivity, moderate sensitivity, and low sensitivity phenotypes towards warfarin (Coumadin), a widely used anticoagulant.