Category Archives: Pharmacogenomics

PharmacogenomicsChoosing the right medication at the right dose for each patient

April 16, 2018

Did you know ... that the sequence of your genome can determine how you respond to certain medications?

Understanding pharmacogenomics, or tailoring a person's medications based on their genome, would not be possible without sequencing the genomes of many people and comparing their responses to medicines.

Oneof the most important uses for DNA sequencing is not to just sequence one human genome - but rather to sequence many human genomes to understand how genomic differences relate to different traits. Some such traits reflect physical characteristics (like eye color), whereas others can be used to help in the clinical care of patients. Scientists in the field of pharmacogenomics study how specific variants in your genome sequence influence your response to medications.

In order for our bodies to use some medicines properly, the cells in our bodies must make a few chemical changes that convert them into an active form, just like we do when we eat food. Then, these active forms of the medicine must get to the right places in the body or inside cells to do the job that we want them to do. If we want to make sure this happens, it makes sense that we would target our bodies' pathways involved in changing the medicine's form or in getting medicines to the right places. For example, you probably know someone who takes an antidepressant. Many of these medicines get to the right places by interacting with a protein called ABCB1,which works like a traffic cop on the outside of your cells.

Given ABCB1's important role in controlling traffic, you might imagine that if someone has a genomic variant that changes the shape or function of their ABCB1 protein, they might have a different response than usual to any number of medicines. We now know that is the case for some antidepressants, as well as other medications like statins for cholesterol and certain chemotherapy medicines. As a result, there are at least 18 pharmacogenomic tests for variants in ABCB1 listed in the NIH's Genetic Test Registry, with suggestions that you be tested for these variants to help determine the correct dose for certain medications.

Video courtesy of Mayo Clinic

Healthcare professionals and researchers are constantly seeking both to optimize medical treatments and to avoid adverse (or negative) reactions to treatments, which are estimated to affect between 7 percentand 14 percentof hospitalized patients. This makes adverse reactions a large cause of added days spent in a hospital, and the fourth leading cause of death in the United States.

One scary example of such an adverse reaction is Stevens-Johnson syndrome (SJS), a severe allergic reaction also called "scalded skin syndrome." It can be caused by infections, but also by very common medications like ibuprofen, anti-seizure medicines, or antibiotics. Patients may go from taking two pain pills to ending up in the hospital burn unit fighting for their lives if SJS progresses to a worse condition called toxic epidermal necrolysis (TEN). TEN is diagnosed when patients have shed at least one-third of the skin off of their bodies. Needless to say, anything we can do to prevent this allergic reaction is vitally important.

In Taiwan, married scientists Wen-Hung Chung (a physician) and Shuen-Iu Hung (an immunologist) noticed that SJS/TEN was much more common in patients taking carbamazepine, used to treat epilepsy and seizures, or allopurinol, used to treat gout. They showed that this was due to genomic variants in the HLA-B gene. Not surprisingly, this gene helps control the immune response. As a result of their work, the country of Thailand has implemented genomic testing before these medications are prescribed. The results of this "pharmacogenomic test" are used to decide whether it is safe to give a specific patient certain medicines, like carbamazepine or allopurinol. Thailand's government even covers the cost of this testing, and the frequency of SJS/TEN has been drastically reduced. We have since learned that different ancestries are associated with different HLA-B genomic variants, so countries may need to take different approaches to monitor which medications are most likely to be linked to SJS/TEN.

Video courtesy of Mayo Clinic

Understanding pharmacogenomics would not be possible without sequencing the genomes of many people and comparing them, and then comparing their response to medicines. But we have also learned that a person's genome sequence is not everything when it comes to medication responses. The human body is a very complicated machine, and the instructions written in our DNA are just part of the process.

There are some cases, as with the breast cancer treatment tamoxifen, where a small study showed that there might be a relationship between someone's response to the medicine and a variant in the CYP2D6 gene. However, this finding did not appear to be true in a larger study that involved many more people. That's why at this time, the U.S. Food and Drug Administration (FDA) labeling for tamoxifen does not recommend CYP2D6 pharmacogenomic testing, but the issue is still being reviewed as more research is conducted.

Another gene in the same CYP family, called CYP2C19, has variations which affect how your body can use clopidogrel (more commonly known as Plavix). This medication is a "blood thinner" which helps prevent blood clots, and thus reduces your risk of strokes or some heart attacks. If your CYP2C19 protein is not working properly due to a mutation in the gene, then you will not be able to process clopidogrel, and you need either a different dose or a different medication. As it turns out, these variants in CYP2C19 are also more common in those with Asian ancestry. Although testing for variants in this gene is also not routinely recommended, you may wish to speak with your healthcare provider about the test if you are given a prescription for clopidogrel, particularly if you have East Asian family members.

As the field of pharmacogenomics develops, more and more clinical trials will test for interactions between our genomes and the medicines we take. If you are interested in participating in such trials, you can search the ClinicalTrials.gov registry and look for ongoing studies with your condition. If you are curious whether any of your medications are known to be associated with pharmacogenomic information, check out the Pharmacogenomics Knowledge Database and speak with your medical care team. And, if you'd like to be part of a national effort along with one million other people that will involve pharmacogenomics research, look into the National Institute of Health's All of Us program.

Posted: April 16, 2018

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April 16: Pharmacogenomics - National Human Genome ...

The English-language neologism omics informally refers to a field of study in biology ending in -omics, such as genomics, proteomics or metabolomics. The related suffix -ome is used to address the objects of study of such fields, such as the genome, proteome or metabolome respectively. Omics aims at the collective characterization and quantification of pools of biological molecules that translate into the structure, function, and dynamics of an organism or organisms.

Functional genomics aims at identifying the functions of as many genes as possible of a given organism. It combines different -omics techniques such as transcriptomics and proteomics with saturated mutant collections.[1]

The suffix -ome as used in molecular biology refers to a totality of some sort; it is an example of a "neo-suffix" formed by abstraction from various Greek terms in -, a sequence that does not form an identifiable suffix in Greek.

The Oxford English Dictionary (OED) distinguishes three different fields of application for the -ome suffix:

The -ome suffix originated as a variant of -oma, and became productive in the last quarter of the 19th century. It originally appeared in terms like sclerome[2] or rhizome.[3] All of these terms derive from Greek words in -,[4] a sequence that is not a single suffix, but analyzable as --, the -- belonging to the word stem (usually a verb) and the - being a genuine Greek suffix forming abstract nouns.

The OED suggests that its third definition originated as a back-formation from mitome,[5] Early attestations include biome (1916)[6] and genome (first coined as German Genom in 1920[7]).[8]

The association with chromosome in molecular biology is by false etymology. The word chromosome derives from the Greek stems ()- "colour" and ()- "body".[8] While "body" genuinely contains the - suffix, the preceding -- is not a stem-forming suffix but part of the word's root. Because genome refers to the complete genetic makeup of an organism, a neo-suffix -ome suggested itself as referring to "wholeness" or "completion".[9]

Bioinformaticians and molecular biologists figured amongst the first scientists to apply the "-ome" suffix widely. Early advocates included bioinformaticians in Cambridge, UK, where there were many early bioinformatics labs such as the MRC centre, Sanger centre, and EBI (European Bioinformatics Institute). For example, the MRC centre carried out the first genome and proteome projects.

Lipidome is the entire complement of cellular lipids, including the modifications made to a particular set of lipids, produced by an organism or system.

Proteome is the entire complement of proteins, including the modifications made to a particular set of proteins, produced by an organism or system.

Glycomics is the comprehensive study of the glycome i.e. sugars and carbohydrates.

Foodomics was defined in 2009 as "a discipline that studies the Food and Nutrition domains through the application and integration of advanced -omics technologies to improve consumer's well-being, health, and knowledge"

Transcriptome is the set of all RNA molecules, including mRNA, rRNA, tRNA, and other non-coding RNA, produced in one or a population of cells.

Inspired by foundational questions in evolutionary biology, a Harvard team around Jean-Baptiste Michel and Erez Lieberman Aiden created the American neologism culturomics for the application of big data collection and analysis to cultural studies.

The word comic does not use the "omics" suffix; it derives from Greek ()- (merriment) + -()- (an adjectival suffix), rather than presenting a truncation of ()-.

Similarly, the word economy is assembled from Greek ()- (household) + ()- (law or custom), and economic(s) from ()- + ()- + -()-. The suffix -omics is sometimes used to create names for schools of economics, such as Reaganomics.

Many omes beyond the original genome have become useful and have been widely adopted by research scientists. Proteomics has become well-established as a term for studying proteins at a large scale. "Omes" can provide an easy shorthand to encapsulate a field; for example, an interactomics study is clearly recognisable as relating to large-scale analyses of gene-gene, protein-protein, or protein-ligand interactions. Researchers are rapidly taking up omes and omics, as shown by the explosion of the use of these terms in PubMed since the mid '90s.[15]

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Omics - Wikipedia

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]

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Irinotecan - Wikipedia