Pharmacogenomics is the study of the role of the
genome
In the fields of molecular biology and genetics, a genome is all the genetic information of an organism. It consists of nucleotide sequences of DNA (or RNA in RNA viruses). The nuclear genome includes protein-coding genes and non-coding g ...
in
drug response. Its name (''
pharmaco-'' + ''
genomics'') reflects its combining of
pharmacology and
genomics. Pharmacogenomics analyzes how the genetic makeup of an individual affects their response to drugs. It deals with the influence of
acquired and
inherited genetic variation on drug response in patients by correlating DNA
mutations (including
single-nucleotide polymorphism
In genetics, a single-nucleotide polymorphism (SNP ; plural SNPs ) is a germline substitution of a single nucleotide at a specific position in the genome. Although certain definitions require the substitution to be present in a sufficiently lar ...
s,
copy number variations
Copy number variation (CNV) is a phenomenon in which sections of the genome are repeated and the number of repeats in the genome varies between individuals. Copy number variation is a type of structural variation: specifically, it is a type of G ...
, and
insertions/deletions) with
pharmacokinetic (drug
absorption,
distribution,
metabolism
Metabolism (, from el, μεταβολή ''metabolē'', "change") is the set of life-sustaining chemical reactions in organisms. The three main functions of metabolism are: the conversion of the energy in food to energy available to run c ...
, and
elimination),
pharmacodynamic (effects mediated through a drug's
biological target
A biological target is anything within a living organism to which some other entity (like an endogenous ligand or a drug) is directed and/or binds, resulting in a change in its behavior or function. Examples of common classes of biological targets ...
s), and/or
immunogenic
Immunogenicity is the ability of a foreign substance, such as an antigen, to provoke an immune response in the body of a human or other animal. It may be wanted or unwanted:
* Wanted immunogenicity typically relates to vaccines, where the injectio ...
endpoints.
Pharmacogenomics aims to develop rational means to optimize
drug therapy
Pharmacotherapy is therapy using pharmaceutical drugs, as distinguished from therapy using surgery (surgical therapy), radiation (radiation therapy), movement (physical therapy), or other modes. Among physicians, sometimes the term ''medical ther ...
, with respect to the patients'
genotype, to ensure maximum efficiency with minimal
adverse effects
An adverse effect is an undesired harmful effect resulting from a medication or other intervention, such as surgery. An adverse effect may be termed a "side effect", when judged to be secondary to a main or therapeutic effect. The term complica ...
.
Through the utilization of pharmacogenomics, it is hoped that
pharmaceutical drug
A medication (also called medicament, medicine, pharmaceutical drug, medicinal drug or simply drug) is a drug used to diagnose, cure, treat, or prevent disease. Drug therapy (pharmacotherapy) is an important part of the medical field an ...
treatments can deviate from what is dubbed as the "one-dose-fits-all" approach. Pharmacogenomics also attempts to eliminate the trial-and-error method of 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
Precision, precise or precisely may refer to:
Science, and technology, and mathematics Mathematics and computing (general)
* Accuracy and precision, measurement deviation from true value and its scatter
* Significant figures, the number of digi ...
and even
personalized medicine
Personalized medicine, also referred to as precision medicine, is a medical model that separates people into different groups—with medical decisions, practices, interventions and/or products being tailored to the individual patient based on the ...
, 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 thereof to a treatment, or act as a predictive tool, it hopes to achieve better treatment outcomes, greater efficacy, minimization of the occurrence of drug toxicities and adverse drug reactions (ADRs). For patients who have lack of therapeutic response 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
Genotyping is the process of determining differences in the genetic make-up (genotype) of an individual by examining the individual's DNA sequence using biological assays and comparing it to another individual's sequence or a reference sequence. ...
or
exome
The exome is composed of all of the exons within the genome, the sequences which, when transcribed, remain within the mature RNA after introns are removed by RNA splicing. This includes untranslated regions of messenger RNA (mRNA), and coding re ...
or whole
genome
In the fields of molecular biology and genetics, a genome is all the genetic information of an organism. It consists of nucleotide sequences of DNA (or RNA in RNA viruses). The nuclear genome includes protein-coding genes and non-coding g ...
sequencing.
Sequencing provides many more data points, including detection of mutations that prematurely terminate the synthesized protein (early
stop codon
In molecular biology (specifically protein biosynthesis), a stop codon (or termination codon) is a codon (nucleotide triplet within messenger RNA) that signals the termination of the translation process of the current protein. Most codons in mess ...
).
[
]
History
Pharmacogenomics was first recognized by Pythagoras
Pythagoras of Samos ( grc, Πυθαγόρας ὁ Σάμιος, Pythagóras ho Sámios, Pythagoras the Samian, or simply ; in Ionian Greek; ) was an ancient Ionian Greek philosopher and the eponymous founder of Pythagoreanism. His politi ...
around 510 BC when he made a connection between the dangers of fava bean ingestion with hemolytic anemia and oxidative stress. This identification was later validated and attributed to deficiency of G6PD
Glucose-6-phosphate dehydrogenase (G6PD or G6PDH) () is a cytosolic enzyme that catalyzes the chemical reaction
: D-glucose 6-phosphate + NADP+ + H2O 6-phospho-D-glucono-1,5-lactone + NADPH + H+
This enzyme participates in the pentose phosp ...
in the 1950s and called favism
Glucose-6-phosphate dehydrogenase deficiency (G6PDD), which is the most common enzyme deficiency worldwide, is an inborn error of metabolism that predisposes to red blood cell breakdown. Most of the time, those who are affected have no symptoms. ...
. Although the first official publication dates back to 1961, circa 1950s marked the unofficial beginnings of this science. Reports of prolonged paralysis and fatal reactions linked to genetic variants in patients who lacked butyryl-cholinesterase ('pseudocholinesterase') following administration of 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 to 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
In biology, epigenetics is the study of stable phenotypic changes (known as ''marks'') that do not involve alterations in the DNA sequence. The Greek prefix '' epi-'' ( "over, outside of, around") in ''epigenetics'' implies features that are ...
while dealing with the effects of multiple genes or even chromosomes
A chromosome is a long DNA molecule with part or all of the genetic material of an organism. In most chromosomes the very long thin DNA fibers are coated with packaging proteins; in eukaryotic cells the most important of these proteins are ...
on drug response. Pharmacogenomics study the inherited genetic differences in drug metabolic pathway
In biochemistry, a metabolic pathway is a linked series of chemical reactions occurring within a cell. The reactants, products, and intermediates of an enzymatic reaction are known as metabolites, which are modified by a sequence of chemical reac ...
s (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
In biology, the word gene (from , ; "... Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a b ...
interactions taking in count allele
An allele (, ; ; modern formation from Greek ἄλλος ''állos'', "other") is a variation of the same sequence of nucleotides at the same place on a long DNA molecule, as described in leading textbooks on genetics and evolution.
::"The chro ...
genes, dominance and gene polymorphism
A gene is said to be polymorphic if more than one allele occupies that gene's locus within a population. In addition to having more than one allele at a specific locus, each allele must also occur in the population at a rate of at least 1% to gen ...
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
The therapeutic index (TI; also referred to as therapeutic ratio) is a quantitative measurement of the relative safety of a drug. It is a comparison of the amount of a therapeutic agent that causes the therapeutic effect to the amount that causes ...
and result in either toxicity or loss of effectiveness.
Drug-metabolizing enzymes
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
Cytochromes P450 (CYPs) are a superfamily of enzymes containing heme as a cofactor that functions as monooxygenases. In mammals, these proteins oxidize steroids, fatty acids, and xenobiotics, and are important for the clearance of various co ...
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
UDP-glucuronosyltransferase 1-1 also known as UGT-1A is an enzyme that in humans is encoded by the ''UGT1A1'' gene.
UGT-1A is a uridine diphosphate glucuronosyltransferase (UDP-glucuronosyltransferase, UDPGT), an enzyme of the glucuronidation pat ...
(a UDP-glucuronosyltransferase
Uridine 5'-diphospho-glucuronosyltransferase ( UDP-glucuronosyltransferase, UGT) is a microsomal glycosyltransferase () that catalyzes the transfer of the glucuronic acid component of UDP-glucuronic acid to a small hydrophobic molecule. This is ...
), DPYD
In enzymology, a dihydropyrimidine dehydrogenase (NADP+) () is an enzyme that catalyzes the chemical reaction
:5,6-dihydrouracil + NADP+ \rightleftharpoons uracil + NADPH + H+
Thus, the two substrates of this enzyme are 5,6-dihydrouracil a ...
, 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
The ATP-binding cassette transporters (ABC transporters) are a transport system superfamily that is one of the largest and possibly one of the oldest gene families. It is represented in all extant phyla, from prokaryotes to humans. ABC transpo ...
, and organic anion transporters.
Pharmacodynamics
Example: VKORC1
The vitamin K epoxide reductase complex subunit 1 (VKORC1
The human gene ''VKORC1'' encodes for the enzyme, Vitamin K epOxide Reductase Complex (VKORC) subunit 1. This enzymatic protein complex is responsible for reducing vitamin K 2,3-epoxide to its active form, which is important for effective clottin ...
) 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
The human leukocyte antigen (HLA) system or complex is a complex of genes on chromosome 6 in humans which encode cell-surface proteins responsible for the regulation of the immune system. The HLA system is also known as the human version of th ...
(HLA) system, also referred to as the major histocompatibility complex (MHC), is a complex of genes important for the adaptive immune system
The adaptive immune system, also known as the acquired immune system, is a subsystem of the immune system that is composed of specialized, systemic cells and processes that eliminate pathogens or prevent their growth. The acquired 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®)
Th
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 barrier 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 leading 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 of 2020 the FDA
The United States Food and Drug Administration (FDA or US FDA) is a federal agency of the Department of Health and Human Services. The FDA is responsible for protecting and promoting public health through the control and supervision of food ...
published th
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 FD
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
The National Institutes of Health, commonly referred to as NIH (with each letter pronounced individually), is the primary agency of the United States government responsible for biomedical and public health research. It was founded in the late ...
-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 United States of America (U.S.A. or USA), commonly known as the United States (U.S. or US) or America, is a country primarily located in North America. It consists of 50 states, a federal district, five major unincorporated territori ...
, the laboratory performing the test much be CLIA CLIA may refer to:
* Chemiluminescent immunoassay
* Clinical Laboratory Improvement Amendments
* Cruise Lines International Association
Cruise Lines International Association (CLIA) is a cruise line trade association. It merged with Internationa ...
-certified. Other regulations may vary by country and state.
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
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
Nomenclature (, ) is a system of names or terms, or the rules for forming these terms in a particular field of arts or sciences. The principles of naming vary from the relatively informal conventions of everyday speech to the internationally ag ...
system is to report haplotypes
A haplotype (haploid genotype) is a group of alleles in an organism that are inherited together from a single parent.
Many organisms contain genetic material ( DNA) which is inherited from two parents. Normally these organisms have their DNA org ...
using a star (*) allele (e.g., CYP2C19
Cytochrome P450 2C19 (abbreviated CYP2C19) is an enzyme protein. It is a member of the CYP2C subfamily of the cytochrome P450 mixed-function oxidase system. This subfamily includes enzymes that catalyze metabolism of xenobiotics, including some p ...
*1/*2). SNPs may be described using their assignment reference SNP cluster ID (rsID) or based on the location of the base pair or amino acid
Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha a ...
impacted.
Phenotype
In 2017 CPIC published results of an expert survey
Survey may refer to:
Statistics and human research
* Statistical survey, a method for collecting quantitative information about items in a population
* Survey (human research), including opinion polls
Spatial measurement
* Surveying, the techniq ...
to standardize terms related to clinical pharmacogenetic test results. Consensus for terms to describe allele functional status, phenotype
In genetics, the phenotype () is the set of observable characteristics or traits of an organism. The term covers the organism's morphology or physical form and structure, its developmental processes, its biochemical and physiological pr ...
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
Pain management is an aspect of medicine and health care involving relief of pain (pain relief, analgesia, pain control) in various dimensions, from acute and simple to chronic and challenging. Most physicians and other health professionals pr ...
, cardiology
Cardiology () is a branch of medicine that deals with disorders of the heart and the cardiovascular system. The field includes medical diagnosis and treatment of congenital heart defects, coronary artery disease, heart failure, valvular h ...
, oncology
Oncology is a branch of medicine that deals with the study, treatment, diagnosis and prevention of cancer. A medical professional who practices oncology is an ''oncologist''. The name's etymological origin is the Greek word ὄγκος ('' ...
, and psychiatry
Psychiatry is the specialty (medicine), medical specialty devoted to the diagnosis, prevention, and treatment of mental disorders. These include various maladaptations related to mood, behaviour, cognition, and perceptions. See glossary of psych ...
. A place may also exist in forensic pathology
Forensic pathology is pathology that focuses on determining the cause of death by examining a corpse. A post mortem examination is performed by a medical examiner or forensic pathologist, usually during the investigation of criminal law cases ...
, 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
Cancer can be treated by surgery, chemotherapy, radiation therapy, hormonal therapy, targeted therapy (including immunotherapy such as monoclonal antibody therapy) and synthetic lethality, most commonly as a series of separate treatments (e.g. ...
, pharmacogenomics tests are used to identify which patients are most likely to respond to certain cancer drugs
Chemotherapy (often abbreviated to chemo and sometimes CTX or CTx) is a type of cancer treatment that uses one or more anti-cancer drugs (chemotherapeutic agents or alkylating agents) as part of a standardized chemotherapy regimen. Chemotherap ...
. 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
''KRAS'' ( Kirsten rat sarcoma virus) is a gene that provides instructions for making a protein called K-Ras, a part of the RAS/MAPK pathway. The protein relays signals from outside the cell to the cell's nucleus. These signals instruct the cel ...
test with cetuximab
Cetuximab, sold under the brand name Erbitux, is an epidermal growth factor receptor (EGFR) inhibitor medication used for the treatment of metastatic colorectal cancer and head and neck cancer. Cetuximab is a chimeric (mouse/human) monoclonal a ...
and EGFR test with gefitinib
Gefitinib, sold under the brand name Iressa, is a medication used for certain breast, lung and other cancers. Gefitinib is an EGFR inhibitor, like erlotinib, which interrupts signaling through the epidermal growth factor receptor (EGFR) in targ ...
. 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
UDP-glucuronosyltransferase 1-1 also known as UGT-1A is an enzyme that in humans is encoded by the ''UGT1A1'' gene.
UGT-1A is a uridine diphosphate glucuronosyltransferase (UDP-glucuronosyltransferase, UDPGT), an enzyme of the glucuronidation pat ...
, TPMT, CDA and CYP2D6
Cytochrome P450 2D6 (CYP2D6) is an enzyme that in humans is encoded by the ''CYP2D6'' gene. ''CYP2D6'' is primarily expressed in the liver. It is also highly expressed in areas of the central nervous system, including the substantia nigra.
CYP2D ...
are now considered as critical issues for patients treated with 5-FU/capecitabine, irinotecan, mercaptopurine/azathioprine, gemcitabine/capecitabine/AraC and tamoxifen, respectively.
In cardiovascular disorders
Cardiovascular disease (CVD) is a class of diseases that involve the heart or blood vessels. CVD includes coronary artery diseases (CAD) such as angina and myocardial infarction (commonly known as a heart attack). Other CVDs include stroke, hea ...
, the main concern is response to drugs including warfarin
Warfarin, sold under the brand name Coumadin among others, is a medication that is used as an anticoagulant (blood thinner). It is commonly used to prevent blood clots such as deep vein thrombosis and pulmonary embolism, and to prevent st ...
, clopidogrel
Clopidogrel — sold under the brand name Plavix, among others — is an antiplatelet medication used to reduce the risk of heart disease and stroke in those at high risk. It is also used together with aspirin in heart attacks and following ...
, beta blocker
Beta blockers, also spelled β-blockers, are a class of medications that are predominantly used to manage abnormal heart rhythms, and to protect the heart from a second heart attack after a first heart attack ( secondary prevention). They are ...
s, and statin
Statins, also known as HMG-CoA reductase inhibitors, are a class of lipid-lowering medications that reduce illness and mortality in those who are at high risk of cardiovascular disease. They are the most common cholesterol-lowering drugs.
Low ...
s.[ In patients with CYP2C19, who take clopidogrel, cardiovascular risk is elevated, leading to medication package insert updates by regulators. In patients with ]type 2 diabetes
Type 2 diabetes, formerly known as adult-onset diabetes, is a form of diabetes mellitus that is characterized by high blood sugar, insulin resistance, and relative lack of insulin. Common symptoms include increased thirst, frequent urinatio ...
, haptoglobin
Haptoglobin (abbreviated as Hp) is the protein that in humans is encoded by the ''HP'' gene. In blood plasma, haptoglobin binds with high affinity to ''free'' hemoglobin released from erythrocytes, and thereby inhibits its deleterious oxidative ...
(Hp) genotyping shows an effect on cardiovascular disease, with Hp2-2 at higher risk and supplemental vitamin E reducing risk by affecting HDL.
In psychiatry, as of 2010, research has focused particularly on 5-HTTLPR and DRD2
Dopamine receptor D2, also known as D2R, is a protein that, in humans, is encoded by the ''DRD2'' gene. After work from Paul Greengard's lab had suggested that dopamine receptors were the site of action of antipsychotic drugs, several groups, i ...
.
Clinical implementation
Initiatives to spur adoption by clinicians include th
Ubiquitous Pharmacogenomics (U-PGx)
program in Europe
Europe is a large peninsula conventionally considered a continent in its own right because of its great physical size and the weight of its history and traditions. Europe is also considered a subcontinent of Eurasia and it is located entirel ...
and the Clinical Pharmacogenetics Implementation Consortium (CPIC) in the United States. In a 2017 survey of European clinicians, in the prior year two-thirds had not ordered a pharmacogenetic test.
In 2010, Vanderbilt University Medical Center
The Vanderbilt University Medical Center (VUMC) is a medical provider with multiple hospitals in Nashville, Tennessee, as well as clinics and facilities throughout Middle Tennessee. VUMC is an independent non-profit organization, but maintains acad ...
launched Pharmacogenomic Resource for Enhanced Decisions in Care and Treatment (PREDICT); in 2015 survey, two-thirds of the clinicians had ordered a pharmacogenetic test.
In 2019, the largest private health insurer, UnitedHealthcare
UnitedHealth Group Incorporated is an American multinational managed healthcare and insurance company based in Minnetonka, Minnesota. It offers health care products and insurance services. UnitedHealth Group is the world's seventh largest c ...
, announced that it would pay for genetic testing to predict response to psychiatric drugs.
In 2020, Canada's
Canada is a country in North America. Its ten provinces and three territories extend from the Atlantic Ocean to the Pacific Ocean and northward into the Arctic Ocean, covering over , making it the world's second-largest country by total ...
4th largest health and dental insurer, Green Shield Canada, announced that it would pay for pharmacogenetic testing and its associated clinical decision support software to optimize and personalize mental health prescriptions.
Reduction of Polypharmacy
A potential role pharmacogenomics may play would be to reduce the occurrence of polypharmacy
Polypharmacy (polypragmasia) is the simultaneous use of multiple medicines by a patient for their conditions. Most commonly it is defined as regularly taking five or more medicines but definitions vary in where they draw the line for the minimum ...
. It is theorized that with tailored drug treatments, patients will not have the need to take several medications that are intended to treat the same condition. In doing so, they could potentially minimize the occurrence of ADRs, have improved treatment outcomes, and can save costs by avoiding purchasing extraneous medications. An example of this can be found in psychiatry
Psychiatry is the specialty (medicine), medical specialty devoted to the diagnosis, prevention, and treatment of mental disorders. These include various maladaptations related to mood, behaviour, cognition, and perceptions. See glossary of psych ...
, where patients tend to be receiving more medications than even age-matched non-psychiatric patients. This has been associated with an increased risk of inappropriate prescribing.
The need for pharmacogenomics tailored drug therapies may be most evident in a survey conducted by the Slone Epidemiology Center at Boston University
Boston University (BU) is a Private university, private research university in Boston, Massachusetts. The university is nonsectarian, but has a historical affiliation with the United Methodist Church. It was founded in 1839 by Methodists with ...
from February 1998 to April 2007. The study elucidated that an average of 82% of adults in the United States are taking at least one medication (prescription or nonprescription drug, vitamin/mineral, herbal/natural supplement), and 29% are taking five or more. The study suggested that those aged 65 years or older continue to be the biggest consumers of medications, with 17-19 % in this age group taking at least ten medications in a given week. Polypharmacy has also shown to have increased since 2000 from 23% to 29%.
Example case studies
''Case A – Antipsychotic adverse reaction''
Patient A has schizophrenia. Their treatment included a combination of ziprasidone, olanzapine, trazodone and benztropine. The patient experienced dizziness and sedation, so they were tapered off ziprasidone and olanzapine, and transitioned to quetiapine. Trazodone was discontinued. The patient then experienced excessive sweating, tachycardia and neck pain, gained considerable weight and had hallucinations. Five months later, quetiapine was tapered and discontinued, with ziprasidone re-introduction into their treatment due to the excessive weight gain. Although the patient lost the excessive weight they gained, they then developed muscle stiffness, cogwheeling
Hypokinesia is one of the classifications of movement disorders, and refers to decreased bodily movement. Hypokinesia is characterized by a partial or complete loss of muscle movement due to a disruption in the basal ganglia. Hypokinesia is a sym ...
, tremors and night sweats. When benztropine was added they experienced blurry vision. After an additional five months, the patient was switched from ziprasidone to aripiprazole. Over the course of 8 months, patient A gradually experienced more weight gain, sedation, developed difficulty with their gait, stiffness, cogwheeling and dyskinetic ocular movements. A pharmacogenomics test later proved the patient had a CYP2D6 *1/*41, which has a predicted phenotype of IM and CYP2C19 *1/*2 with a predicted phenotype of IM as well.
''Case B – Pain Management''
Patient B is a woman who gave birth by caesarian section. Her physician prescribed codeine for post-caesarian pain. She took the standard prescribed dose, however experienced nausea and dizziness while she was taking codeine. She also noticed that her breastfed infant was lethargic and feeding poorly. When the patient mentioned these symptoms to her physician, they recommended that she discontinue codeine use. Within a few days, both the patient and her infant's symptoms were no longer present. It is assumed that if the patient underwent a pharmacogenomic test, it would have revealed she may have had a duplication of the gene CYP2D6 placing her in the Ultra-rapid metabolizer (UM) category, explaining her ADRs to codeine use.
''Case C – FDA Warning on Codeine Overdose for Infants''
On February 20, 2013, the FDA released a statement addressing a serious concern regarding the connection between children who are known as CYP2D6 UM and fatal reactions to codeine following tonsillectomy
Tonsillectomy is a list of surgical procedures, surgical procedure in which both palatine tonsils are fully removed from the back of the throat. The procedure is mainly performed for recurrent tonsillitis, throat infections and obstructive sleep ...
and/or adenoidectomy
Adenoidectomy is the surgical removal of the adenoid for reasons which include impaired breathing through the nose, chronic infections, or recurrent earaches. The effectiveness of removing the adenoids in children to improve recurrent nasal sympto ...
(surgery to remove the tonsils and/or adenoids). They released their strongest Boxed Warning to elucidate the dangers of CYP2D6 UMs consuming codeine. Codeine is converted to morphine by CYP2D6, and those who have UM phenotypes are at danger of producing large amounts of morphine due to the increased function of the gene. The morphine can elevate to life-threatening or fatal amounts, as became evident with the death of three children in August 2012.
Challenges
Although there appears to be a general acceptance of the basic tenet of pharmacogenomics amongst physicians and healthcare professionals, several challenges exist that slow the uptake, implementation, and standardization of pharmacogenomics. Some of the concerns raised by physicians include:
* Limitation on how to apply the test into clinical practices and treatment;
* A general feeling of lack of availability of the test;
* The understanding and interpretation of evidence-based research;
* Combining test results with other patient data for prescription optimization; and
* Ethical, legal and social issues.
Issues surrounding the availability of the test include:
* ''The lack of availability of scientific data'': Although there are considerable number of DME involved in the metabolic pathways of drugs, only a fraction have sufficient scientific data to validate their use within a clinical setting; and
* ''Demonstrating the cost-effectiveness of pharmacogenomics'': Publications for the pharmacoeconomics
Pharmacoeconomics refers to the scientific discipline that compares the value of one pharmaceutical drug or drug therapy to another. It is a sub-discipline of health economics. A pharmacoeconomic study evaluates the cost (expressed in monetary te ...
of pharmacogenomics are scarce, therefore sufficient evidence does not at this time exist to validate the cost-effectiveness and cost-consequences of the test.
Although other factors contribute to the slow progression of pharmacogenomics (such as developing guidelines for clinical use), the above factors appear to be the most prevalent. Increasingly substantial evidence and industry body guidelines for clinical use of pharmacogenetics have made it a population wide approach to precision medicine. Cost, reimbursement, education, and easy use at the point of care remain significant barriers to widescale adoption.
Controversies
Race-based Medicine
Race and health refers to how being identified with a specific race influences health. Race is a complex concept that has changed across chronological eras and depends on both self-identification and social recognition. In the study of race and ...
There has been call to move away from race and ethnicity in medicine and instead use genetic ancestry as a way to categorize patients. Some allele
An allele (, ; ; modern formation from Greek ἄλλος ''állos'', "other") is a variation of the same sequence of nucleotides at the same place on a long DNA molecule, as described in leading textbooks on genetics and evolution.
::"The chro ...
s that vary in frequency between specific populations have been shown to be associated with differential responses to specific drugs. As a result, some disease-specific guidelines only recommend pharmacogenetic testing for populations where high-risk alleles are more common and, similarly, certain insurance companies will only pay for pharmacogenetic testing for beneficiaries of high-risk populations.
Genetic Exceptionalism
In the early 2000’s, handling genetic information as exceptional, including legal or regulatory protections, garnered strong support. It was argued that genomic information may need special policy and practice protections within the context of electronic health records (EHRs). In 2008, the Genetic Information Nondiscrimination Act (GINA) was enacted to protect patients from health insurance companies discriminating against an individual based on genetic information.
More recently it has been argued that genetic exceptionalism Genetic exceptionalism is the belief that genetic information is special and so must be treated differently from other types of medical data or other personally identifiable information.
For example, patients are able to obtain information about ...
is past its expiration date as we move into a blended genomic/big data era of medicine, yet exceptionalism practices continue to permeate clinical healthcare today. Garrison et al recently relayed a call to action to update verbiage from genetic exceptionalism to genomic contextualism in that we recognize a fundamental duality of genetic information. This allows room in the argument for different types of genetic information to be handled differently while acknowledging that genomic information is similar and yet distinct from other health-related information. Genomic contextualism would allow for a case-by-case analysis of the technology and the context of its use (e.g., clinical practice, research, secondary findings).
Others argue that genetic information is indeed distinct from other health-related information but not to the extent of requiring legal/regulatory protections, similar to other sensitive health-related data such as HIV status. Additionally, Evans et al. argue that the EHR has sufficient privacy standards to hold other sensitive information such as social security numbers and that the fundamental nature of an EHR is to house highly personal information. Similarly, a systematic review reported that the public had concern over privacy of genetic information, with 60% agreeing that maintaining privacy was not possible; however, 96% agreed that a direct-to-consumer testing company had protected their privacy, with 74% saying their information would be similarly or better protected in an EHR. With increasing technological capabilities in EHRs, it is possible to mask or hide genetic data from subsets of providers and there is not consensus on how, when, or from whom genetic information should be masked. Rigorous protection and masking of genetic information is argued to impede further scientific progress and clinical translation into routine clinical practices.
Future
Computational advances have enabled cheaper and faster sequencing. Research has focused on combinatorial chemistry Combinatorial chemistry comprises chemical synthetic methods that make it possible to prepare a large number (tens to thousands or even millions) of compounds in a single process. These compound libraries can be made as mixtures, sets of individua ...
, genomic mining, omic technologies, and high throughput screening
High-throughput screening (HTS) is a method for scientific experimentation especially used in drug discovery and relevant to the fields of biology, materials science and chemistry. Using robotics, data processing/control software, liquid handli ...
.
As the cost per genetic test decreases, the development of personalized drug therapies will increase. Technology now allows for genetic analysis of hundreds of target genes involved in medication metabolism and response in less than 24 hours for under $1,000. This a huge step towards bringing pharmacogenetic technology into everyday medical decisions. Likewise, companies like deCODE genetics
deCODE genetics ( is, Íslensk erfðagreining) is a biopharmaceutical company based in Reykjavík, Iceland. The company was founded in 1996 by Kári Stefánsson with the aim of using population genetics studies to identify variations in the hum ...
, MD Labs Pharmacogenetics, Navigenics and 23andMe
23andMe Holding Co. is a publicly held personal genomics and biotechnology company based in South San Francisco, California. It is best known for providing a direct-to-consumer genetic testing service in which customers provide a saliva sample ...
offer genome scans. The companies use the same genotyping
Genotyping is the process of determining differences in the genetic make-up (genotype) of an individual by examining the individual's DNA sequence using biological assays and comparing it to another individual's sequence or a reference sequence. ...
chips that are used in GWAS studies and provide customers with a write-up of individual risk for various traits and diseases and testing for 500,000 known SNPs. Costs range from $995 to $2500 and include updates with new data from studies as they become available. The more expensive packages even included a telephone session with a genetics counselor to discuss the results.
Ethics
Pharmacogenetics has become a controversial issue in the area of bioethics
Bioethics is both a field of study and professional practice, interested in ethical issues related to health (primarily focused on the human, but also increasingly includes animal ethics), including those emerging from advances in biology, m ...
. Privacy and confidentiality are major concerns. The evidence of benefit or risk from a genetic test may only be suggestive, which could cause dilemmas for providers. Drug development may be affected, with rare genetic variants possibly receiving less research. Access and patient autonomy are also open to discussion.
Web-based Resources
See also
* Genomics
**Chemogenomics
Chemogenomics, or chemical genomics, is the systematic screening of targeted chemical libraries of small molecules against individual drug target families (e.g., GPCRs, nuclear receptors, kinases, proteases, etc.) with the ultimate goal of id ...
** Clinomics
** Genetic engineering
**Toxicogenomics Toxicogenomics is a subdiscipline of pharmacology that deals with the collection, interpretation, and storage of information about gene and protein activity within a particular cell or tissue of an organism in response to exposure to toxic substan ...
** Cancer pharmacogenomics
*Metabolomics
Metabolomics is the scientific study of chemical processes involving metabolites, the small molecule substrates, intermediates, and products of cell metabolism. Specifically, metabolomics is the "systematic study of the unique chemical fingerprin ...
*Pharmacovigilance
Term Given By Tushar Sharma (UPES Batch 2025)
Pharmacovigilance (PV, or PhV), also known as drug safety, is the pharmaceutical science relating to the "collection, detection, assessment, monitoring, and prevention" of adverse effects with pharma ...
*Population groups in biomedicine
Race and health refers to how being identified with a specific race influences health. Race is a complex concept that has changed across chronological eras and depends on both self-identification and social recognition. In the study of race and ...
* Toxgnostics
Toxgnostics is part of personalized medicine as it describes the guiding principles for the discovery of pharmacogenomic biomarker tests, also referred to as companion diagnostic tests, which identify if an individual patient is likely to suffer s ...
* Medical terminology
** LOINC
Logical Observation Identifiers Names and Codes (LOINC) is a database and universal standard for identifying medical laboratory observations. First developed in 1994, it was created and is maintained by the Regenstrief Institute, a US nonprofit me ...
** SNOMED CT
SNOMED CT or SNOMED Clinical Terms is a systematically organized computer-processable collection of medical terms providing codes, terms, synonyms and definitions used in clinical documentation and reporting. SNOMED CT is considered to be the mo ...
** HPO
** HGVS
* HL7
** FHIR
* Genetic testing
References
Further reading
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