Category Archives: Pharmacogenomics

AmpliSeq On-Demand Panels: Coming up with different design combinations for a panel requires time and effort. And you guys are doing all the work I like the idea of ordering only the genes that I see more

- Dr. William G. Kearns, PhD Founder & Director AdvaGenix Rockville, US

AmpliSeq On-Demand Panels: Coming up with different design combinations for a panel requires time and effort. And you guys are doing all the work I like the idea of ordering only the genes that I want, and being able to roll with it.

AmpliSeq On-Demand Panels: the majority of the projects we provide service for has only a few samples...it is good to have a small pack size...we have been limited because of the cost...this may see more

- Dr. Adam Ameur Department of Immunology, Genetics and Pathology Uppsala University

AmpliSeq On-Demand Panels: the majority of the projects we provide service for has only a few samples...it is good to have a small pack size...we have been limited because of the cost...this may possibly open up other studies...looking at larger genes with fewer samples Our results look very promising with even coverage across all samples and 100% of known variants detected"

AmpliSeq On-Demand Panels: "..you can kind of cherry pick genes of interest and design your own panel...so I like it"

- Dr. Michal Mikula Department of Genetics Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology Warsaw, Poland

AmpliSeq On-Demand Panels: "..you can kind of cherry pick genes of interest and design your own panel...so I like it"

AmpliSeq On-Demand Panels: Cost was a limiting factor for panels with a large number of amplicons. For labs who need to change their gene content frequently, the lower price for oligos is really see more

- Dr. Pan Zhang, PhD, MD Director, Sequencing and Microarray Center Coriell Institute for Medical Research

AmpliSeq On-Demand Panels: Cost was a limiting factor for panels with a large number of amplicons. For labs who need to change their gene content frequently, the lower price for oligos is really great

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Ion AmpliSeq Designer

General Description, Overview, and Opportunities

Pharmacogenomics has increasingly become an area of interest to clinicians because of the potential to tailor pharmacotherapy based on genetic variations in patients. Pharmacogenomics is one of the key aspects of personalized medicine, focusing on how an individual's DNA affects the way they respond to medications. All individuals have different genetic make-up so they respond differently to the same medication. Based on this insight, pharmacogenomics allows customized treatment for a wide range of health problems including; cardiovascular disease, Alzheimer's disease, cancer, HIV/AIDS, and asthma. Often, drug choice and dosage require experimentation (trial and error) in order to find the best treatment option. With pharmacogenomics testing, the need for this experimentation is decreased. As a result, the process becomes faster and more cost-effective and the possibility of adverse events caused by the wrong drug choice or dosage is significantly reduced.

One avenue for implementing pharmacogenomic is through medication therapy management (MTM), where pharmacists assess and evaluate a patient's complete medication therapy regimen. By gathering key pieces of information, e.g. which medications and supplements a patient is currently taking, pharmacists can assess current treatment and suggest alternative therapies.

As medication experts and POC service providers, pharmacists can educate physicians and patients and perform the actual sample collection to be utilized for genetic testing. The broad application of pharmacogenomics to personalized medicine will improve patient outcomes and lower healthcare costs.

Test Features

Pharmacies require a lab partner to provide clinically relevant data and interpret results for physicians. Most tests screens all well-established pharmacogenomics genes in a single, cost-effective test. Results are delivered quickly via intuitive, clinically relevant, medically actionable report. The data provides lifetime utility of data, thereby decreasing the need for future testing.

Community pharmacists routinely perform point of care services and can assist patients by:

Performing a buccal swab in minutes

Send the collected DNA to the lab

Interpret results and discuss with physicians

Contact the patient to explain the results and any changes in therapy

Companies

Pharmacist Resources and Training

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Pharmacogenomics - NCPA

Cytochrome P450 2C9 (abbreviated CYP2C9) is an enzyme that in humans is encoded by the CYP2C9 gene.[5][6]

CYP2C9 is an important cytochrome P450 enzyme with a major role in the oxidation of both xenobiotic and endogenous compounds. CYP2C9 makes up about 18% of the cytochrome P450 protein in liver microsomes (data only for antifungal). Some 100 therapeutic drugs are metabolized by CYP2C9, including drugs with a narrow therapeutic index such as warfarin and phenytoin and other routinely prescribed drugs such as acenocoumarol, tolbutamide, losartan, glipizide, and some nonsteroidal anti-inflammatory drugs. By contrast, the known extrahepatic CYP2C9 often metabolizes important endogenous compound such as serotonin and, owing to its epoxygenase activity, various polyunsaturated fatty acids, converting these fatty acids to a wide range of biological active products.[7][8]

In particular, CYP2C9 metabolizes arachidonic acid to the following eicosatrienoic acid epoxide (termed EETs) stereoisomer sets: 5R,6S-epoxy-8Z,11Z,14Z-eicosatetrienoic and 5S,6R-epoxy-8Z,11Z,14Z-eicosatetrienoic acids; 11R,12S-epoxy-8Z,11Z,14Z-eicosatetrienoic and 11S,12R-epoxy-5Z,8Z,14Z-eicosatetrienoic acids; and 14R,15S-epoxy-5Z,8Z,11Z-eicosatetrainoic and 14S,15R-epoxy-5Z,8Z,11Z-eicosatetrainoic acids. It likewise metablizes docosahexaenoic acid to epoxydocosapentaenoic acids (EDPs; primarily 19,20-epoxy-eicosapentaenoic acid isomers [i.e. 10,11-EDPs]) and eicosapentaenoic acid to epoxyeicosatetraenoic acids (EEQs, primarily 17,18-EEQ and 14,15-EEQ isomers).[9] Animal model and a limited number of human studies implicate these epoxides in reducing hypertension; protecting against the Myocardial infarction and other insults to the heart; promoting the growth and metastasis of certain cancers; inhibiting inflammation; stimulating blood vessel formation; and possessing a variety of actions on neural tissues including modulating Neurohormone release and blocking pain perception (see epoxyeicosatrienoic acid and epoxygenase pages).[8]

In vitro studies on human and animal cells and tissues and in vivo animal model studies indicate that certain EDPs and EEQs (16,17-EDPs, 19,20-EDPs, 17,18-EEQs have been most often examined) have actions which often oppose those of another product of CYP450 enzymes (e.g. CYP4A1, CYP4A11, CYP4F2, CYP4F3A, and CYP4F3B) viz., 20-Hydroxyeicosatetraenoic acid (20-HETE), principally in the areas of blood pressure regulation, blood vessel thrombosis, and cancer growth (see 20-Hydroxyeicosatetraenoic acid, Epoxyeicosatetraenoic acid, and Epoxydocosapentaenoic acid sections on activities and clinical significance). Such studies also indicate that the EPAs and EEQs are: 1) more potent than EETs in decreasing hypertension and pain perception; 2) more potent than or equal in potency to the EETs in suppressing inflammation; and 3) act oppositely from the EETs in that they inhibit angiogenesis, endothelial cell migration, endothelial cell proliferation, and the growth and metastasis of human breast and prostate cancer cell lines whereas EETs have stimulatory effects in each of these systems.[10][11][12][13] Consumption of omega-3 fatty acid-rich diets dramatically raises the serum and tissue levels of EDPs and EEQs in animals as well as humans and in humans are by far the most prominent change in the profile of PUFA metabolites caused by dietary omega-3 fatty acids.[10][13][14]

CYP2C9 may also metabolize linoleic acid to the potentially very toxic products, vernolic acid (also termed leukotoxin) and coronaric acid (also termed isoleukotoxin); these linoleic acid epoxides cause multiple organ failure and acute respiratory distress in animal models and may contribute to these syndromes in humans.[8]

9-tetrahydrocannabinol (9-THC), cannabidiol (CBD) and cannabinol (CBN), the three major constituents in cannabis, are found to be direct inhibitors for CYP2C9.[15]

Genetic polymorphism exists for CYP2C9 expression because the CYP2C9 gene is highly polymorphic. More than 50 single nucleotide polymorphisms (SNPs) have been described in the regulatory and coding regions of the CYP2C9 gene;[16] some of them are associated with reduced enzyme activity compared with wild type in vitro.[citation needed]

Multiple in vivo studies also show that several mutant CYP2C9 genotypes are associated with significant reduction of in metabolism and daily dose requirements of selected CYP2C9 substrate. In fact, adverse drug reactions (ADRs) often result from unanticipated changes in CYP2C9 enzyme activity secondary to genetic polymorphisms. Especially for CYP2C9 substrates such as warfarin and phenytoin, diminished metabolic capacity because of genetic polymorphisms or drug-drug interactions can lead to toxicity at normal therapeutic doses.[17][18]

Allele frequencies(%) of CYP2C9 polymorphism

Most inhibitors of CYP2C9 are competitive inhibitors. Noncompetitive inhibitors of CYP2C9 include nifedipine,[19][20] phenethyl isothiocyanate,[21] medroxyprogesterone acetate[22] and 6-hydroxyflavone. It was indicated that the noncompetitive binding site of 6-hydroxyflavone is the reported allosteric binding site of the CYP2C9 enzyme.[23]

Following is a table of selected substrates, inducers and inhibitors of CYP2C9. Where classes of agents are listed, there may be exceptions within the class.

Inhibitors of CYP2C9 can be classified by their potency, such as:

CYP2C9 attacks various long-chain polyunsaturated fatty acids at their double (i.e. alkene) bonds to form epoxide products that act as signaling molecules. It along with CYP2C8, CYP2C19, CYP2J2, and possibly CYP2S1 are the principle enzymes which metabolizes 1) arachidonic acid to various epoxyeicosatrienoic acids (also termed EETs); 2) linoleic acid to 9,10-epoxy octadecaenoic acids (also termed vernolic acid, linoleic acid 9:10-oxide, or leukotoxin) and 12,13-epoxy-octadecaenoic (also termed coronaric acid, linoleic acid 12,13-oxide, or isoleukotoxin); 3) docosohexaenoic acid to various epoxydocosapentaenoic acids (also termed EDPs); and 4) eicosapentaenoic acid to various epoxyeicosatetraenoic acids (also termed EEQs).[8] Animal model studies implicate these epoxides in regulating: hypertension, Myocardial infarction and other insults to the heart, the growth of various cancers, inflammation, blood vessel formation, and pain perception; limited studies suggest but have not proven that these epoxides may function similarly in humans (see epoxyeicosatrienoic acid and epoxygenase pages).[8] Since the consumption of omega-3 fatty acid-rich diets dramatically raises the serum and tissue levels of the EDP and EEQ metabolites of the omega-3 fatty acid, i.e. docosahexaenoic and eicosapentaenoic acids, in animals and humans and in humans is the most prominent change in the profile of PUFA metabolites caused by dietary omega-3 fatty acids, EPA and EEQs may be responsible for at least some of the beneficial effects ascribed to dietary omega-3 fatty acids.[36][37][38]

PDB gallery

1og2: STRUCTURE OF HUMAN CYTOCHROME P450 CYP2C9

1og5: STRUCTURE OF HUMAN CYTOCHROME P450 CYP2C9

1r9o: Crystal Structure of P4502C9 with Flurbiprofen bound

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CYP2C9 - Wikipedia

IrinotecanClinical dataTrade namesCamptosar (US), Campto (EU), Onivyde (liposomal)AHFS/Drugs.comMonographMedlinePlusa608043Pregnancycategory

O=C7OCC=6C(=O)N2C(c1nc5c(c(c1C2)CC)cc(OC(=O)N4CCC(N3CCCCC3)CC4)cc5)=C/C=6[C@@]7(O)CC

Irinotecan, sold under the brand name Camptosar among others, is a medication used to treat colon cancer and small cell lung cancer.[1] For colon cancer it is used either alone or with fluorouracil.[1] For small cell lung cancer it is used with cisplatin.[1] It is given by slow injection into a vein.[1]

Common side effects include diarrhea, vomiting, bone marrow suppression, hair loss, shortness of breath, and fever.[1] Other severe side effects include blood clots, colon inflammation, and allergic reactions.[1] Those with two copies of the UGT1A1*28 gene variant are at higher risk for side effects.[1] Use during pregnancy can result in harm to the baby.[1] Irinotecan is in topoisomerase inhibitor family of medication.[2] It works by blocking topoisomerase 1 which results in DNA damage and cell death.[1]

Irinotecan was approved for medical use in the United States in 1996.[1] It is on the World Health Organization's List of Essential Medicines, the most effective and safe medicines needed in a health system.[3] In the United Kingdom it is available as a generic medication and costs the NHS about 114.00 pounds per 100mg.[2] It is made from the natural compound camptothecin.[1]

Its main use is in colon cancer, in particular, in combination with other chemotherapy agents. This includes the regimen FOLFIRI, which consists of infusional 5-fluorouracil, leucovorin, and irinotecan. The regimen XELIRI consists of capecitabine and irinotecan.[4][5]

The most significant adverse effects of irinotecan are severe diarrhea and extreme suppression of the immune system.[6]

Irinotecan-associated diarrhea is severe and clinically significant, sometimes leading to severe dehydration requiring hospitalization or intensive care unit admission. This side-effect is managed with the aggressive use of antidiarrheals such as loperamide or co-phenotrope with the first loose bowel movement.

The immune system is adversely impacted by irinotecan. This is reflected in dramatically lowered white blood cell counts in the blood, in particular the neutrophils. The patient may experience a period of neutropenia (a clinically significant decrease of neutrophils in the blood) while the bone marrow increases white cell production to compensate.

Irinotecan is activated by hydrolysis to SN-38, an inhibitor of topoisomerase I. This is then inactivated by glucuronidation by uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1). The inhibition of topoisomerase I by the active metabolite SN-38 eventually leads to inhibition of both DNA replication and transcription.[6]

The molecular action of irinotecan occurs by trapping a subset of topoisomerase-1-DNA cleavage complexes, those with a guanine +1 in the DNA sequence.[7] One irinotecan molecule stacks against the base pairs flanking the topoisomerase-induced cleavage site and poisons (inactivates) the topoisomerase 1 enzyme.[7]

Click on genes, proteins and metabolites below to link to respective articles. [ 1]

Irinotecan is converted by an enzyme into its active metabolite SN-38, which is in turn inactivated by the enzyme UGT1A1 by glucuronidation.

People with variants of the UGT1A1 called TA7, also known as the "*28 variant", express fewer UGT1A1 enzymes in their liver and often have Gilbert's syndrome. During chemotherapy, they effectively receive a larger than expected dose because their bodies are not able to clear irinotecan as fast as others. In studies this corresponds to higher incidences of severe neutropenia and diarrhea.[8]

In 2004, a clinical study was performed that both validated prospectively the association of the *28 variant with greater toxicity and the ability of genetic testing in predicting that toxicity before chemotherapy administration.[8]

In 2005, the FDA made changes to the labeling of irinotecan to add pharmacogenomics recommendations, such that irinotecan recipients with a homozygous (both of the two gene copies) polymorphism in UGT1A1 gene, to be specific, the *28 variant, should be considered for reduced drug doses.[9] Irinotecan is one of the first widely used chemotherapy agents that is dosed according to the recipient's genotype.[10]

Irinotecan received accelerated approval from the U.S. Food and Drug Administration (FDA) in 1996 and full approval in 1998.[11][12]

During development, it was known as CPT-11.

A liposome encapsulated version of irinotecan sold as Onivyde, was approved by FDA in October 2015 to treat metastatic pancreatic cancer.[13] It gained EU approval in October 2016.[14]

Read more:
Irinotecan - Wikipedia

Some smokers have more of an urge to light up right after they wake up, and UW-Madison researchers have identified a reason: genetic variation in a substance that breaks down nicotine in the brain.

The finding, by scientists at UW-Madison and Washington University in St. Louis, adds to growing research on genetic links to how much people smoke, how hard it is for them to quit and how likely they are to develop lung cancer.

Most of the attention has focused on genetic variation in enzymes that metabolize nicotine in the liver. Some studies suggest that dozens of genes could influence how addicted people become to smoking.

The new understanding about FMO3, an enzyme that metabolizes nicotine in the brain, could someday allow researchers to tailor tobacco cessation treatments to individual patients or develop new drugs to target the enzyme.

The research clearly suggests that its not just one or two big players here, but that a lot of genes may contribute to these outcomes, said Tim Baker, director of research at UW-Madisons Center for Tobacco Research and Intervention.

Despite a steady decline in smoking in recent years, tobacco remains the leading cause of preventable death, according to the Centers for Disease Control and Prevention.

About 17.3 percent of Wisconsin adults smoked in 2015. Thats down from 20.9 percent in 2011. Still, nearly 800,000 adults and adolescents in the state continue to light up, resulting in about 7,700 deaths a year, according to the state Department of Health Services.

Nationally, 17.5 percent of adults smoked in 2015, and smoking causes 480,000 deaths a year, the CDC says. More than half of American smokers attempt to quit each year, but only 6 percent succeed.

The brain enzyme study, published earlier this year in The Pharmacogenomics Journal, involved 1,558 smokers, most of them in a study at UW-Madison of people who were trying to quit.

Smokers with genes that produce more FMO3, causing nicotine to be broken down more quickly in the brain, were more likely to say they smoke first thing in the morning a key indicator of nicotine dependence.

Even if they have a home smoking ban, they will go out into their porch or to the garage to have their cigarette right away, as soon as they get up, Baker said.

Smokers with certain genetic types of the liver enzymes respond better to nicotine replacement therapy, researchers have found. Its too early to tell if the same might be true for the brain enzyme.

The genetic information could eventually help more smokers quit, but Baker said they shouldnt wait.

Regardless of their genetic status, although some people are at greater risk than others, any kind of smoking is dangerous and they should do whatever they can to quit now, he said.

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UW-Madison study links nicotine addiction to genetic variation in ... - Madison.com

MediMap is a one-time Pharmacogenomics (or "PGx") test that may indicate how a person will respond to specific prescription medications. Your MediMap test results can help guide your healthcare providers to ensure better medication choices and doses based on your genetic makeup... leading to more effective illness management and improved health. The future of medicine is about putting into practice the knowledge that with prescription medicines and dosage amounts, one size does NOT fit all.

The MediMap test is available for all ages; everyone in the family including newborns can benefit from pharmacogenomics testing.

Please note: some studies may overlap; for example, a MediMap multi-drug panel may include the specific drug(s) you were looking to be tested for within a condition-specific panel. A genetic counselor will go over your best options during your consult.

What is pharmacogenomics?+

Pharmacogenomics is the study of how people's genes affect their response to medications.The term pharmacogenomics (also called PGx) is a combination of pharmacology (the study of medications) and genomics (the study of how peoples genetic information can influence their health).PGx may be used to help choose the best medications and doses for you.

What is MediMap?+

MediMap is a pharmacogenomic test that helps guide you and your healthcare providers to better medication choices and doses for you. Until recently, most medicines have been developed and given to patients in a "one size fits all" approach.However, people respond differently to medications due, in part, to their genetic makeup. While some people will find a medication helpful, others may not respond to that medication at all. Some people will need a dose that is higher or lower than what is usually prescribed. Even others may have negative side effects (called adverse drug reactions).MediMap looks at specific genetic changes (called variants) that influence a persons response to many medications.

Does MediMap cover all prescription medications?+

While the number of personalized medicines increases steadily every year, not all medications can yet be connected with genetic changes that influence a persons response to medications.Also, there are other medications (besides those included in our tests) that have been reported to be affected by pharmacogenomic variants. However, at this time, there is not enough evidence available to include them on our reports. To help you better understand differences between evidence levels, we differentiate between "actionable" and "informative" information on our reports."Actionable" means there are expert recommendations to help guide clinical treatment; and "informative" means there is insufficient evidence, at this time, and clinical use of this information is optional.You can see which prescription medications are covered in each MediMap tests on our MediMap test comparison sheet.

Which MediMap test is best for me?+

At your appointment, you will meet with a genetic counselor to discuss available testing options. Factors to consider may include: medications you are currently taking, those you might be prescribed in the future, and a history of medication side effects or ineffectiveness. Our goal is for you to have a good understanding of how pharmacogenomic testing may help you, and allow you and your physician to make the best decisions for you.

Are my results confidential?+

Yes. The results will be entered into the secure Inova electronic medical record, and a copy of the report will be mailed to your home. You are responsible for sharing your test results with your healthcare providers.

What will happen to my DNA sample?+

Your DNA sample will be kept for at least 90 days after the MediMap report has been sent to you. At that time, the sample will be disposed or de-identified (name and other identifiers are removed) depending on your selection at the time you authorize the test. If your sample is de-identified, it may be used for quality control purposes, to develop new tests, or for educational activities. No clinical tests other than MediMap will be performed using your DNA sample.

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MediMap - pharmacogenomic testing for adults and children ...