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pharmacogenomics

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Why Pharmacogenomics ("PGX")?

GENETWORx was created with the targeted focus of impacting and improving people’s lives by empowering them and their physicians with the information and medicinal results they need through pharmacogenomic testing.

GENETWORx Laboratory recognized a gap in healthcare services between the lab and pharmacy: Every person’s body and genetic make-up is different—and therefore why shouldn’t their medications follow suit? Knowing a person’s genetic makeup can indicate how their body will process an metabolize drugs. The metabolism of a drug can have important consequences on its therapeutic effect or its toxicity. For instance, whether the drug will be metabolized by the body too quickly or too slowly to be effective.

Without knowing which medication will be the optimal choice, it can be trial and error for a physician—they pick a medication based on their past experience or drug prescribing information in the hope that the patient’s body responds effectively to it. Personalized medicine using pharmacogenomic testing takes some of the guesswork out of medication effectiveness.

What is Pharmacogenomics ("Pgx")?

Pharmacogenomics is the study of how DNA impacts individual responses to medication.
  • Pharmacogenomics is able to improve clinical outcomes as well as provide financial value to the health system. There are many compelling studies that found significant cost-savings value from introducing pharmacogenomics to physicians and patients.1
  • GENETWORx is an expert in pharmacogenomics lab testing, detecting genetic differences that affect the metabolism of therapeutic medications and the possibility for adverse events.2

Having a list of medications and a list of potential medication-medication interactions, gene-medication interactions, and medication-gene-medication interactions, along with this new genetic information, gives a prescriber a better understanding of why their patient may respond to a medication in a particular way. In other words: A more effective medication the first time around, eliminating the time, energy, and money wasted trying to find the “right” medication for a patient.

GENETWORx is a pharmacogenomic lab and tests 30 genes to help identify mutations that may affect a person’s metabolism and/or response to medications. Once the pharmacogenomic analysis, conducted via a simple cheek swab sample, is complete, a Personalized Medication Report is reviewed by a pharmacist at GENETWORx and prepared for the prescriber so that they can identify potential gene-medication interactions, medication-medication interactions, as well as medication-gene-medication interactions. GENETWORx reports provide a pharmacogenomic analysis along with a Personalized Medication Guide, that list medications by specialty in categories of: Use as Directed, Use with Caution, or Recommend Alternative Medication. This list can be used for helping a prescriber choose new or alternative medications for their patient. The report is a powerful tool to help healthcare providers and their patients determine the best course of treatment.

Dear Ms. Helber,

What a wonderful genetic testing service GENETWORx provides, and what great employees you have there! My husband, Mark, had genetic testing with you through his orthopedist’s office 6 years ago, as he was heading for a knee replacement in his early 50s (25 years of serious running was not a good thing). Because of his medication allergies, the orthopedist decided to do genetic testing to check on the pain meds to be prescribed. As a result, he canceled Mark’s surgery because all the meds he could prescribe for the post-surgery pain were contraindicated. Mark turned out to be a poor CYP2D6 metabolizer, and nothing was going to reduce the pain sufficiently for him to complete rehab. The orthopedist said that he didn’t want to leave Mark in worse shape than before the surgery, which was in hindsight a good thing.

All that genetic information six years ago was wonderful to have, and Stacey B. our GENETWORx pharmacist was terrific in helping us decipher it. Mark’s had more issues since, especially as he has intractable migraines and is constantly taking pain meds, so we and his latest neurologist decided to redo the genetic testing. Stacey said GENETWORx had increased the number of genes it tests for. Another super-helpful choice on our part! When we had access to it, we both thoroughly read through and highlighted specific meds he should avoid, and yep, he’d been prescribed some of them in the intervening six years, with less than positive results.

Stacey has been a treasure during the past several months, helping us check on additional meds, explaining Promedications versus non Promedications, and just generally being amazing. At this point there have been a number of emails between us, and I can really tell that she’s not only an excellent pharmacist but a truly wonderful person, and a great asset to you and GENETWORx. One critical thing, especially during these times of working remote, is that Stacey can write complete, thoroughly explanatory emails, which is not a common skill. We’ve been really appreciative to have her assistance and her kindness as we negotiate Mark’s worsening health.

The last months have been a difficult time for everyone, so Mark and I both immensely appreciate the services you still provide at GENETWORx. Thanks again, keep up the good work, and stay well.”

- Lynn

Medication Management Test Menu

Cytochrome P450 Enzymes: The Cytochrome P450 enzyme system is one of several metabolic systems which plays a major role in the metabolism of medications. A medication that is metabolized by a certain enzyme is a substrate of that enzyme. Some medications are also promedications of a certain enzyme, meaning it becomes “active” in the body after it is metabolized. Mutations in the specific enzymes can cause individuals to metabolize medications at different rates. Metabolic rates are classified for each enzyme as Normal Metabolizer, Rapid Metabolizer, Intermediate Metabolizer and Poor Metabolizer.

GeneDescription
Cytochrome P450 EnzymesThe Cytochrome P450 enzyme system is one of several metabolic systems which plays a major role in the metabolism of medication. A medication that is metabolized by a certain enzyme is a substrate of that enzyme. Some medications are also pro medications of a certain enzyme, meaning it becomes “active” in the body after it is metabolized. Mutations in the specific enzymes can cause individuals to metabolize medications at different rates. Metabolic rates are classified for each enzyme as Normal Metabolizer, Rapid Metabolizer, Intermediate Metabolizer and Poor Metabolizer.
CYP1A2This gene encodes for the formation of CYP1A2 enzymes influencing variability in metabolism of approximately 9% of medications. Some examples of CYP1A2 substrates are caffeine, clozapine, cyclobenzaprine, lidocaine, olanzapine, propranolol, ropivacaine, tizanidine, zileuton.
CYP2B6This gene encodes for the formation of CYP2B6 enzymes influencing variability in metabolism of approximately 7% of medications. Some examples of CYP2B6 substrates are bupropion, efavirenz, irinotecan, ifosfamide, methadone, cyclophosphamide, ketamine, nevirapine, propofol, selegiline, testosterone.
CYP2C19This gene encodes for the formation of CYP2C19 enzymes influencing variability in metabolism of approximately 10 to 15% of medications. Some examples of 2C19 substrates are esomeprazole, lansoprazole, citalopram, escitalopram, amitriptyline, diazepam, phenytoin, carisoprodol, clopidogrel, sertraline, pantoprazole, moclobemide, imipramine, voriconazole.
CYP2C8This gene encodes for the formation of CYP2C8 enzymes influencing variability in metabolism of approximately 5% of medication. Some examples of CYP2C8 substrates are amiodarone, paclitaxel, pioglitazone, rosiglitazone, repaglinide, torsemide.
CYP2C9This gene encodes for the formation of CYP2C9 enzymes influencing variability in metabolism of approximately 15% of medication. Some examples of CYP2C9 substrates are meloxicam, losartan, glipizide, glyburide, phenytoin, warfarin and torsemide.
CYP2D6This gene encodes for the formation of CYP2D6 enzymes influencing variability in metabolism of approximately 25-30% of medication. Some examples of CYP2D6 substrates are fluoxetine, paroxetine, aripiprazole, risperidone, duloxetine, amphetamine, metoprolol, tamoxifen and codeine.
CYP3A4/CYP3A5 This gene encodes for the formation of CYP3A4/5 enzymes influencing variability in metabolism of approximately 40% of medications. Some examples of CYP3A4/5 substrates are clarithromycin, clonazepam, diazepam, etravirine, loratadine, diltiazem, simvastatin, carbamazepine, cilostazol, aripiprazole, salmeterol, tamoxifen, trazodone, vemurafenib, zolpidem.

Additional Pharmacokinetic and Pharmacodynamic Genes

GeneDescription
ABCB1ABCB1 (ATP binding cassette subfamily B) encodes for the formation of intestinal efflux transporter P-glycoprotein and is a major contributor in the intestinal absorption of ABCB1 substrates. Poor and intermediate ABCB1 phenotypes may have an increased likelihood of therapeutic failure compared to patients with a normal phenotype and taking ABCB1 substrates. Example Substrates: copidogrel, aliskiren, ambrisentan, colchicine, dabigatran etexilate, digoxin, everolimus, fexofenadine, imatinib, lapatinib, maraviroc, nilotinib, posaconazole, ranolazine, saxagliptin, sirolimus, sitagliptin, talinolol, tolvaptan, topotecan.
ABCG2 ABCG2 (ATP binding cassette subfamily G2) encodes for the formation of intestine, liver, placenta, and the blood–brain barrier efflux transporters in the form of homodimers in the plasma membrane and actively extrudes a wide variety of chemically unrelated compounds from the cells. This protein protects our cells and tissues against various xenobiotics. Example Substrates: daunorubicin, doxorubicin, topotecan, rosuvastatin, sulfasalazine
ADRA2A ADRA2A (Adrenoceptor Alpha 2A) gene plays a critical role in regulating neurotransmitter release from sympathetic nerves and from neurons that release the hormone and neurotransmitter norepinephrine in the central nervous system. Variants in the gene have been linked to the clinical effectiveness of ADHD medications. Additional studies have shown other variants associated with an increased risk for hypertension. Variants in ADRA2A are thought to be present in a quarter of the caucasian population.
APOEAPOE (Apolipoprotein E) gene encodes for the formation of apolipoprotein E which combines with fats (lipids) in the body to form lipoproteins. Lipoproteins are responsible for forming cholesterol and other fats found through the bloodstream. Studies have shown individuals who carry one or more copies of APOE-4 have a reduced therapeutic response to lipid-lowering medications (statins). The APOE-4 allele has shown to have an increased risk of high LDL cholesterol and both cardiovascular disease and Alzheimer’s disease.
COMTCatechol-O-Methyltransferase (COMT) is an enzyme that inactivates catecholamines, such as epinephrine, norepinephrine and dopamine. COMT regulates cognitive function, memory, mood and pain perception. Up to 60% of depressed patients do not respond completely to antidepressants and up to 30% do not respond at all. A variety of medications, such as nicotine replacement therapy (NRT), entacapone, opioids, SSRIs and antipsychotics, may be directly or indirectly impacted by the change in catecholamines inactivation.
DBH Dopamine Beta-Hydroxylase (DBH) gene encodes for the formation dopamine beta-hydroxylase protein. DBH protein catalyzes the hydroxylase of dopamine to norepinephrine and is primarily located in the adrenal medulla and in postganglionic sympathetic neurons. Variations in the DBH gene have been shown to be a risk factor for psychiatric disorders and addiction.
ANKK1/
DRD2/Taq1A
ANKK1 gene is linked to dopamine receptor D2 (DRD2). Dopamine (DA) is a neurotransmitter in the brain, which controls feeling of wellbeing. This sensation results from dopamine and other neurotransmitters such as serotonin, opioids, and other brain chemicals.
Dopamine increases the motivation for food cravings and appetite mediation. The DRD2/ANKK1-Taq1A polymorphism modulates the density of the DRD2 dopamine receptors. Carriers of the A1 allele have shown up to 30% reduced receptor capacity, correlating to a predisposition for individuals to seek addictive behaviors or substances to compensate this deficiency in the dopaminergic system; Examples include binge eating (e.g. fat, refined carbohydrates, salt, caffeine, etc.) and compulsive and impulsive behaviors (e.g. sexual activity, gambling and use of alcohol, medications, opiates, tobacco etc.).
DPYDThis gene encodes the dihydropyrimidine dehydrogenase protein, 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, 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.
GRIK4GRIK4 (glutamate receptor, ionotropic, kainate 4) is the gene that encodes KA1, a type of neurotransmitter receptor subunit that joins together with other subunits to form glutamate receptors. These receptors are located on cells in the brain and are involved in enhancing cell-cell communication, which may play a role in major depressive disorder. This type of receptor primarily binds glutamate, a major neurotransmitter involved in developmental growth, learning and memory. Although the effect of variations in GRIK4 on KA1 function and expression are not fully known, KA1 may play a role in modulating the therapeutic effect of antidepressants. Mutations in GRIK4 may impact patients with major depressive disorder who take citalopram. Patients being considered for citalopram initiation or who have experienced treatment resistance or failure with citalopram should be considered for GRIK4 testing.
HTR2AHTR2A is a post-synaptic serotonin receptor that binds serotonin and is involved in amplification of excitatory signals to other neurons in the brain. Polymorphisms of this gene may affect antidepressant and antipsychotic response and risk of adverse effects. HTR2A polymorphisms can help predict which patients may be more likely to experience SSRI-induced adverse effects and provide supplemental information to determine if patients will adequately respond to therapy.
HTR2C HTR2C is a G-protein coupled serotonin receptor located on the X chromosome. Mutations in this receptor may be useful in predicting which patients are at risk for adverse events from medications such as olanzapine.
IL28B IL28B, also called interferon, lambda 3, is the strongest baseline predictor of response to PEG-interferon-alpha-containing regimens in HCV genotype 1 patients. Patients with the favorable response genotype increased likelihood of response (higher SVR rate) to PEG-interferon-alpha-containing regimens as compared to patients with unfavorable response genotype. Consider implications before initiating PEG-IFN alpha and RBV containing regimens.
ITGB3ITGB3 encodes the gene for beta 3 integrin. Mutations in this gene influence the efficacy of medications such as clopidogrel.
OPRK1Kappa 1 opioid receptor (OPRK1) is a pharmacodynamic receptor that is partly responsible for opioid effectiveness and is associated with pain sensitivity, substance dependence and abuse.
OPRM1Mu 1 opioid receptor (OPRM1) is a pharmacodynamic receptor that is partly responsible for opioid effectiveness and is associated with pain sensitivity, substance dependence and abuse. The most analyzed genetic variants have shown an association with opioid effectiveness, naltrexone efficacy in the treatment of alcoholism and addiction risk to opioids, including heroin. Patients beginning naltrexone treatment for alcohol dependence would be good candidates for OPRM1 testing. Testing can also help predict opioid response and dose requirements. Testing can also help assess opioid addiction risk.
SLCO1B1SLCO1B1 (also known as OAT1B1) encodes for the formation of influx transporter that moves medications into cells. Variations in SLCO1B1 may affect the blood levels of medications that are substrates for this transporter. Some examples of SLCO1B1 transported medications are: atorvastatin, bosentan, ezetimibe, fluvastatin, glyburide, SN-38 (active metabolite of irinotecan), rosuvastatin, simvastatin acid, pitavastatin, pravastatin, repaglinide, rifampin, valsartan, olmesartan
UGT1A1Uridine diphosphate (UDP)-glucuronosyl transferase 1A1 (UGT1A1) is responsible for bilirubin conjugation with glucuronic acid. UGT1A1 is a pharmacogene and patients with reduced UGT1A1 enzyme activity are at risk for adverse outcomes with certain medications. The FDA medication labels for nilotinib, pazopanib, and belinostat all contain warnings for an increased risk (incidence) of adverse outcomes in patients who have UGT1A1 alleles associated with reduced activity.
UGT2B15UDP-glucuronosyltransferase 2B15 is an enzyme that in humans is encoded by the UGT2B15 gene. The UGTs are of major importance in the conjugation and subsequent elimination of potentially toxic xenobiotics and endogenous compounds. Polymorphisms have been associated with variation in medication metabolism, including some medications used for mental health disorders, PPAR agonist (Thiazolidinediones), and clearance of oxazepam or lorazepam.
VKORC1Vitamin K epoxide complex subunit 1 (VKORC1) is the enzyme that activates Vitamin K. Mutations in VKORC1 are associated with deficiencies in vitamin-K-dependent clotting factors. A particular VKORC1 variant (-1939G>A) leads to increased sensitivity to warfarin. VKORC1 mutation accounts for 25-44% of warfarin dose variability and is typically tested for at the same time as 2C9 when warfarin is being considered.
Factor II Prothrombin Genetic ProfilingThis test detects a genetic change in the Factor II gene called Factor II Prothrombin. Patients with this Prothrombin variant are at an increased risk of blood clot formation (thrombosis) when exposed to other risk factors such as smoking, pregnancy, obesity, oral contraceptive use, and immobility. The risk is approximately 3-10 times higher in individuals who have one copy of the genetic variant. The risk in people who carry two copies of the genetic variant is unknown. Individuals who do not have a Factor II Prothrombin mutation may still be at increased risk. Other changes in the Factor II gene that were not tested for, changes in other genes, and non-genetic factors may still increase your risk for thrombosis.
Factor V Leiden Mutation TestThis test detects a genetic change in the Factor V gene called Factor V Leiden. Individuals who have this variant are at an increased risk of blood clot formation. This risk is approximately 2-10 times higher in individuals who have one copy of the genetic variant, and greater than 10 times higher for individuals who carry two copies of the genetic variant. Individuals who do not have the Factor V Leiden mutation may still be at increased risk. Other changes in the Factor V gene that were not tested for, changes in other genes, and non-genetic factors may still increase your risk for thrombosis.
MTHFR Mutation TestingThis test detects two genetic changes in the MTHFR gene. Individuals who are found to have two mutations are at an increased risk for serious blood clot formation. Individuals who have only one or no copies of either genetic change in the MTHFR gene may still be at increased risk. Other changes in the MTHFR gene that were not tested for, changes in other genes, and non-genetic factors may still increase your risk for thrombosis.

Pharmacogenomics

Panel Discussion

Pharmacogenomics is making true personalized medicine a reality. A GENETWORx PGx test helps your doctor tailor a medication treatment plan specifically in line with your DNA profile, avoiding potential drug and dosing issues. A PGx test aims to eliminate trial and error prescribing, significantly reduce side effects associated with medication errors and save you and your doctor time and money. See this recent panel discussion for a deep dive into how pharmacogenomics can help you today.

For more information on our testing capabilities or for instructions on the gathering of samples, please contact GENETWORx by: