pharmacogenomics pharmacogenomics pharmacogenomics is the study of the role of the genome in drug response. its name (pharmaco- + genomics) reflects its combining of pharmacology and genomics. pharmacogenomics analyzes how the genetic makeup of a patient affects their response to drugs. it deals with the influence of acquired and inherited genetic variation on drug response, by correlating dna mutations (including single-nucleotide polymorphisms, copy number variations, and insertions/deletions) with pharmacokinetic (drug absorption, distribution, metabolism, and elimination), pharmacodynamic (effects mediated through a drug's biological targets), and/or immunogenic endpoints. part of a series ongenetics key components chromosome dna rna genome heredity mutation nucleotide variation outline index history and topics introduction history evolution (molecular) population genetics mendelian inheritance quantitative genetics molecular genetics research geneticist dna sequencing genetic engineering genomics ( template) medical genetics branches of genetics personalized medicine personalized medicine category pharmacogenomics aims to develop rational means to optimize drug therapy, with regard to the patients' genotype, to achieve maximum efficiency with minimal adverse effects. it is hoped that by using pharmacogenomics, pharmaceutical drug treatments can deviate from what is dubbed as the "one-dose-fits-all" approach. pharmacogenomics also attempts to eliminate trial-and-error in prescribing, allowing physicians to take into consideration their patient's genes, the functionality of these genes, and how this may affect the efficacy of the patient's current or future treatments (and where applicable, provide an explanation for the failure of past treatments). such approaches promise the advent of precision medicine and even personalized medicine, in which drugs and drug combinations are optimized for narrow subsets of patients or even for each individual's unique genetic makeup. whether used to explain a patient's response (or lack of it) to a treatment, or to act as a predictive tool, it hopes to achieve better treatment outcomes and greater efficacy, and reduce drug toxicities and adverse drug reactions (adrs). for patients who do not respond to a treatment, alternative therapies can be prescribed that would best suit their requirements. in order to provide pharmacogenomic recommendations for a given drug, two possible types of input can be used: genotyping, or exome or whole genome sequencing. sequencing provides many more data points, including detection of mutations that prematurely terminate the synthesized protein (early stop codon). history pharmacogenomics was first recognized by pythagoras around 510 bc when he made a connection between the dangers of fava bean ingestion with hemolytic anemia and oxidative stress. in the 1950s, this identification was validated and attributed to deficiency of g6pd, and called favism. although the first official publication was not until 1961, the unofficial beginnings of this science were around the 1950s. reports of prolonged paralysis and fatal reactions linked to genetic variants in patients who lacked butyrylcholinesterase ('pseudocholinesterase') following succinylcholine injection during anesthesia were first reported in 1956. the term pharmacogenetic was first coined in 1959 by friedrich vogel of heidelberg, germany (although some papers suggest it was 1957 or 1958). in the late 1960s, twin studies supported the inference of genetic involvement in drug metabolism, with identical twins sharing remarkable similarities in drug response compared to fraternal twins. the term pharmacogenomics first began appearing around the 1990s. the first fda approval of a pharmacogenetic test was in 2005 (for alleles in cyp2d6 and cyp2c19). pharmacogenetics vs. pharmacogenomics the term pharmacogenomics is often used interchangeably with pharmacogenetics. although both terms relate to drug response based on genetic influences. pharmacogenomics encompasses a more genome-wide association approach, incorporating genomics and epigenetics while dealing with the effects of multiple genes or even chromosomes on drug response. pharmacogenomics study the inherited genetic differences in drug metabolic pathways (and other pharmacological principles, like enzymes, messengers and receptors) which can affect individual responses to drugs, both in terms of therapeutic effect as well as adverse effects. pharmacogenetics in the other hand focuses on single drug-gene interactions taking in count allele genes, dominance and gene polymorphism in order to understand the better use of a drug on a single patient or population. mechanisms of pharmacogenetic interactions pharmacokinetics pharmacokinetics involves the absorption, distribution, metabolism, and elimination of pharmaceutics. these processes are often facilitated by enzymes such as drug transporters or drug metabolizing enzymes (discussed more in-depth below). variation in dna loci responsible for producing these enzymes can alter their expression or activity so that their functional status changes. an increase, decrease, or loss of function for transporters or metabolizing enzymes can ultimately alter the amount of medication within the body. this may result in deviation from the medication's therapeutic window and result in either toxicity or loss of effectiveness. drug-metabolizing enzymes the majority of clinically-actionable pharmacogenetic variation occurs in genes that code for drug-metabolizing enzymes, including those involved in both phase i and phase ii metabolism. the cytochrome p450 enzymes are important for the hepatic metabolism of many medications and are highly polymorphic. additional drug-metabolizing enzymes that have been implicated in pharmacogenetic interactions include ugt1a1 (a udp-glucuronosyltransferase), dpyd, and tpmt. drug transporters many medications rely on transporters to cross cellular membranes in order to move between body fluid compartments such as the blood, gut lumen, bile, urine, brain, and cerebrospinal fluid. the major transporters include the solute carrier, atp-binding cassette, and organic anion transporters. example: vkorc1 the vitamin k epoxide reductase complex subunit 1 (vkorc1) is responsible for the pharmacodynamics of warfarin. vkorc1 along with cyp2c9 are useful for identifying the risk of bleeding during warfarin administration. warfarin works by inhibiting vkor, which is encoded by the vkorc1 gene. individuals with polymorphism in this have an affected response to warfarin treatment. immunologic the human leukocyte antigen (hla) system, also referred to as the major histocompatibility complex (mhc), is a complex of genes important for the adaptive immune system. mutations in the hla complex have been associated with an increased risk of developing hypersensitivity reactions in response to a medication. clinical pharmacogenomics resources clinical pharmacogenetics implementation consortium (cpic) the clinical pharmacogenetics implementation consortium (cpic) is "an international consortium of individual volunteers and a small dedicated staff who are interested in facilitating use of pharmacogenetic tests for patient care. cpic’s goal is to address barriers to clinical implementation of pharmacogenetic tests by creating, curating, and posting freely available, peer-reviewed, evidence-based, updatable, and detailed gene/drug clinical practice guidelines. cpic guidelines follow standardized formats, include systematic grading of evidence and clinical recommendations, use standardized terminology, are peer-reviewed, and are published in a journal (in partnership with clinical pharmacology and therapeutics) with simultaneous posting to cpicpgx.org, where they are regularly updated." the cpic guidelines are "designed to help clinicians understand how available genetic test results should be used to optimize drug therapy, rather than whether tests should be ordered. a key assumption underlying the cpic guidelines is that clinical high-throughput and pre-emptive (pre-prescription) genotyping will become more widespread, and that clinicians will be faced with having patients’ genotypes available even if they have not explicitly ordered a test with a specific drug in mind. cpic’s guidelines, processes and projects have been endorsed by several professional societies." table of pharmacogenetic associations in february 2020 the fda published the table of pharmacogenetic associations. for the gene-drug pairs included in the table, "the fda has evaluated and believes there is sufficient scientific evidence to suggest that subgroups of patients with certain genetic variants, or genetic variant-inferred phenotypes (such as affected subgroup in the table below), are likely to have altered drug metabolism, and in certain cases, differential therapeutic effects, including differences in risks of adverse events." "the information in this table is intended primarily for prescribers, and patients should not adjust their medications without consulting their prescriber. this version of the table is limited to pharmacogenetic associations that are related to drug metabolizing enzyme gene variants, drug transporter gene variants, and gene variants that have been related to a predisposition for certain adverse events. the fda recognizes that various other pharmacogenetic associations exist that are not listed here, and this table will be updated periodically with additional pharmacogenetic associations supported by sufficient scientific evidence." table of pharmacogenomic biomarkers in drug labeling the fda table of pharmacogenomic biomarkers in drug labeling lists fda-approved drugs with pharmacogenomic information found in the drug labeling. "biomarkers in the table include but are not limited to germline or somatic gene variants (polymorphisms, mutations), functional deficiencies with a genetic etiology, gene expression differences, and chromosomal abnormalities; selected protein biomarkers that are used to select treatments for patients are also included." sequence2script sequence2script is a "free online tool to help healthcare providers and clinical laboratories translate pharmacogenetic test results into clinically useful recommendations." this tool "creates a report that outlines medication and dosing recommendations based on a patient’s known genotypes. the recommendations made by this tool are based on expert, peer-reviewed guidelines developed by the cpic, the dutch pharmacogenetics working group (dpwg), and us food & drug administration (fda). all you need to do is enter the patient’s known genetic information and any medications they are currently taking, and sequence2script will compile the recommendations from these sources into a single report that can be reviewed online or printed out." sequence2script was developed by the psychiatric pharmacogenomics laboratory in the department of medical genetics at the university of calgary. pharmgkb the pharmacogenomics knowledgebase (pharmgkb) is an "nih-funded resource that provides information about how human genetic variation affects response to medications. pharmgkb collects, curates and disseminates knowledge about clinically actionable gene-drug associations and genotype-phenotype relationships." phenoconversion calculator the university of florida college of pharmacy developed the prop™ pharmacogenetics calculator to "help clinicians integrate a standardized method of assessing cyp2d6 phenoconversion into practice when a cyp2d6 genotype is available." commercial pharmacogenetic testing laboratories there are many commercial laboratories around the world who offer pharmacogenomic testing as a laboratory developed test (ldts). the tests offered can vary significantly from one lab to another, including genes and alleles tested for, phenotype assignment, and any clinical annotations provided. with the exception of a few direct-to-consumer tests, all pharmacogenetic testing requires an order from an authorized healthcare professional. in order for the results to be used in a clinical setting in the united states, the laboratory performing the test much be clia-certified. other regulations may vary by country and state. final consensus terms for allele functional status and phenotype direct-to-consumer pharmacogenetic testing direct-to-consumer (dtc) pharmacogenetic tests allow consumers to obtain pharmacogenetic testing without an order from a prescriber. dtc pharmacogenetic tests are generally reviewed by the fda to determine the validity of test claims. the fda maintains a list of dtc genetic tests that have been approved. common pharmacogenomic-specific nomenclature genotype there are multiple ways to represent a pharmacogenomic genotype. a commonly used nomenclature system is to report haplotypes using a star (*) allele (e.g., cyp2c19 *1/*2). single-nucleotide polymorphisms (snps) may be described using their assignment reference snp cluster id (rsid) or based on the location of the base pair or amino acid impacted. phenotype in 2017 cpic published results of an expert survey to standardize terms related to clinical pharmacogenetic test results. consensus for terms to describe allele functional status, phenotype for drug metabolizing enzymes, phenotype for drug transporters, and phenotype for high-risk genotype status was reached. applications the list below provides a few more commonly known applications of pharmacogenomics: improve drug safety, and reduce adrs; tailor treatments to meet patients' unique genetic pre-disposition, identifying optimal dosing; improve drug discovery targeted to human disease; and improve proof of principle for efficacy trials. pharmacogenomics may be applied to several areas of medicine, including pain management, cardiology, oncology, and psychiatry. a place may also exist in forensic pathology, in which pharmacogenomics can be used to determine the cause of death in drug-related deaths where no findings emerge using autopsy. in cancer treatment, pharmacogenomics tests are used to identify which patients are most likely to respond to certain cancer drugs. in behavioral health, pharmacogenomic tests provide tools for physicians and care givers to better manage medication selection and side effect amelioration. pharmacogenomics is also known as companion diagnostics, meaning tests being bundled with drugs. examples include kras test with cetuximab and egfr test with gefitinib. beside efficacy, germline pharmacogenetics can help to identify patients likely to undergo severe toxicities when given cytotoxics showing impaired detoxification in relation with genetic polymorphism, such as canonical 5-fu. in particular, genetic deregulations affecting genes coding for dpd, ugt1a1, tpmt, cda and cyp2d6 are now considered as critical issues for patients treated with 5-fu/capecitabine, irinotecan, mercaptopurine/azathioprine, gemcitabine/capecitabine/arac