Pharmacogenomics, often abbreviated "PGx", 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 point mutations, copy number variations, and structural variations) with pharmacokinetic (drug absorption, distribution, metabolism, and elimination), pharmacodynamic (effects mediated through a drug's biological targets), and immunogenic endpoints.
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 effectiveness 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).
Pharmacogenetics vs. pharmacogenomics The term pharmacogenomics is often used interchangeably with pharmacogenetics. Although both terms relate to drug response based on genetic influences, there are differences between the two. Pharmacogenetics is limited to monogenic phenotypes (i.e., single gene-drug interactions). Pharmacogenomics refers to polygenic drug response phenotypes and encompasses transcriptomics, proteomics, and metabolomics.
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 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 in the body and at the site of action. 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 enzyme family is responsible for metabolism of 70–80% of all medications used clinically. CYP3A4, CYP2C9, CYP2C19, and CYP2D6 are major CYP enzymes involved in drug metabolism and are all known to be 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. Transporters that have been shown to influence response to medications include OATP1B1 (SLCO1B1) and breast cancer resistance protein (BCRP) (ABCG2).
Pharmacodynamics Pharmacodynamics refers to the impact a medication has on the body, or its mechanism of action.
Drug targets Drug targets are the specific sites where a medication carries out its pharmacological activity. The interaction between the drug and this site results in a modification of the target that may include inhibition or potentiation. Most of the pharmacogenetic interactions that involve drug targets are within the field of oncology and include targeted therapeutics designed to address somatic mutations (see also Cancer Pharmacogenomics). For example, EGFR inhibitors like gefitinib (Iressa) or erlotinib (Tarceva) are only indicated in patients carrying specific mutations to EGFR.Iressa [package insert]. Wilmington, DE: Astra Zeneca; 2021.Tarceva [package insert]. Northbrook, IL: OSI Pharmaceuticals, LLC; 2016.
Germline mutations in drug targets can also influence response to medications, though this is an emerging subfield within pharmacogenomics. One well-established gene-drug interaction involving a germline mutation to a drug target is warfarin (Coumadin) and VKORC1, which codes for vitamin K epoxide reductase (VKOR). Warfarin binds to and inhibits VKOR, which is an important enzyme in the vitamin K cycle. Inhibition of VKOR prevents reduction of vitamin K, which is a cofactor required in the formation of coagulation factors II, VII, IX and X, and inhibitors protein C and S. A more recent example demonstrated that genetic variation in the GLP1R and GIPR receptor genes has implications for GLP-1 receptor agonist efficacy and risk of side effects.
Off-target sites Medications can have off-target effects (typically unfavorable) that arise from an interaction between the medication and/or its metabolites and a site other than the intended target. Genetic variation in the off-target sites can influence this interaction. The main example of this type of pharmacogenomic interaction is glucose-6-phosphate-dehydrogenase (G6PD). G6PD is the enzyme involved in the first step of the pentose phosphate pathway which generates NADPH (from NADP). NADPH is required for the production of reduced glutathione in erythrocytes and it is essential for the function of catalase. Glutathione and catalase protect cells from oxidative stress that would otherwise result in cell lysis. Certain variants in G6PD result in G6PD deficiency, in which cells are more susceptible to oxidative stress. When medications that have a significant oxidative effect are administered to individuals who are G6PD deficient, they are at an increased risk of erythrocyte lysis that presents as hemolytic anemia.
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 certain medications.
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."
U.S. Food and Drug Administration
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."
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."
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 must be CLIA-certified. Other regulations may vary by country and state.
Direct-to-consumer pharmacogenetic testing