The terms
pharmacogenomicsPharmacogenomics is the branch of pharmacology which deals with the influence of genetic variation on drug response in patients by correlating gene expression or single-nucleotide polymorphisms with a drug's efficacy or toxicity...
and
pharmacogenetics tend to be used interchangeably, and a precise, consensus definition of either remains elusive. Pharmacogenetics is generally regarded as the study or clinical testing of
genetic variationGenetic variation, variation in alleles of genes, occurs both within and among populations. Genetic variation is important because it provides the “raw material” for natural selection.- Among individuals within a population :...
that gives rise to differing response to
drugA drug, broadly speaking, is any substance that, when absorbed into the body of a living organism, alters normal bodily function. There is no single, precise definition, as there are different meanings in drug control law, government regulations, medicine, and colloquial usage.In pharmacology, a...
s, while
pharmacogenomicsPharmacogenomics is the branch of pharmacology which deals with the influence of genetic variation on drug response in patients by correlating gene expression or single-nucleotide polymorphisms with a drug's efficacy or toxicity...
is the broader application of genomic technologies to new
drug discoveryIn the fields of medicine, biotechnology and pharmacology, drug discovery is the process by which drugs are discovered and/or designed.In the past most drugs have been discovered either by identifying the active ingredient from traditional remedies or by serendipitous discovery...
and further characterization of older drugs.
Much of current clinical interest is at the level of pharmacogenetics, involving variation in genes involved in,
drug metabolismDrug metabolism is the metabolism of drugs, their biochemical modification or degradation, usually through specialized enzymatic systems. This is a form of xenobiotic metabolism. Drug metabolism often converts lipophilic chemical compounds into more readily excreted polar products...
with a particular emphasis on improving drug safety.
The terms
pharmacogenomicsPharmacogenomics is the branch of pharmacology which deals with the influence of genetic variation on drug response in patients by correlating gene expression or single-nucleotide polymorphisms with a drug's efficacy or toxicity...
and
pharmacogenetics tend to be used interchangeably, and a precise, consensus definition of either remains elusive. Pharmacogenetics is generally regarded as the study or clinical testing of
genetic variationGenetic variation, variation in alleles of genes, occurs both within and among populations. Genetic variation is important because it provides the “raw material” for natural selection.- Among individuals within a population :...
that gives rise to differing response to
drugA drug, broadly speaking, is any substance that, when absorbed into the body of a living organism, alters normal bodily function. There is no single, precise definition, as there are different meanings in drug control law, government regulations, medicine, and colloquial usage.In pharmacology, a...
s, while
pharmacogenomicsPharmacogenomics is the branch of pharmacology which deals with the influence of genetic variation on drug response in patients by correlating gene expression or single-nucleotide polymorphisms with a drug's efficacy or toxicity...
is the broader application of genomic technologies to new
drug discoveryIn the fields of medicine, biotechnology and pharmacology, drug discovery is the process by which drugs are discovered and/or designed.In the past most drugs have been discovered either by identifying the active ingredient from traditional remedies or by serendipitous discovery...
and further characterization of older drugs.
Pharmacogenetics and adverse drug reactions
Much of current clinical interest is at the level of pharmacogenetics, involving variation in genes involved in,
drug metabolismDrug metabolism is the metabolism of drugs, their biochemical modification or degradation, usually through specialized enzymatic systems. This is a form of xenobiotic metabolism. Drug metabolism often converts lipophilic chemical compounds into more readily excreted polar products...
with a particular emphasis on improving drug safety. The wider use of pharmacogenetic testing is viewed by many as an outstanding opportunity to improve prescribing safety and efficacy. Driving this trend are the 106,000 deaths and 2.2 Million serious events caused by adverse drug reactions in the US each year (Lazarou 1998). As such ADRs are responsible for 5-7% of hospital admissions in the US and Europe, lead to the withdrawal of 4% of new medicines and cost society an amount equal to the costs of drug treatment (Ingelman-Sundberg 2005). Comparisons of the list of drugs most commonly implicated in adverse drug reactions with the list of metabolizing enzymes with known
polymorphismPolymorphism in biology occurs when two or more clearly different phenotypes exist in the same population of a species — in other words, the occurrence of more than one form or morph...
s found that drugs commonly involved in adverse drug reactions were also those that were metabolized by enzymes with known polymorphisms (see Phillips, 2001). The decision to use pharmacogenetic techniques is influenced by the relative costs of
genotypingGenotyping refers to the process of determining the genotype of an individual by the use of biological assays. Current methods of doing this include PCR, DNA sequencing, ASO probes, and hybridization to DNA microarrays or beads...
technologies and the cost of providing a treatment to a patient with an incompatible genotype.
History
The first observations of genetic variation in drug response date from the 1950s, involving the muscle relaxant
suxamethonium chlorideSuxamethonium chloride is a medication used to induce muscle relaxation, usually to make endotracheal intubation possible. Suxamethonium is sold under the trade names Anectine and Scoline.Suxamethonium acts as a depolarizing neuromuscular blocker...
, and drugs metabolized by
N-acetyltransferaseN-acetyltransferase is an enzyme that catalyzes the transfer of acetyl groups from acetyl-CoA to arylamines. They have wide specificity for aromatic amines, particularly serotonin, and can also catalyze acetyl transfer between arylamines without CoA. EC 2.3.1.5....
. One in 3500
CaucasiansThe term Caucasian race has been used to denote the general physical type of some or all of the indigenous populations of Europe, North Africa, the Horn of Africa, West Asia, Central Asia, and South Asia...
has less efficient variant of the
enzymeEnzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process are called substrates, and the enzyme converts them into different molecules, called the products. Almost all processes in a biological cell need enzymes to occur at...
(
butyrylcholinesteraseButyrylcholinesterase, also known as BCHE or BuChE, is an enzyme that, in humans, is encoded by the BCHE gene. Butyrylcholinesterase is also called serum cholinesterase. It is very similar to the neuronal acetylcholinesterase. Butyrylcholine is a synthetic compound and does not occur in the body...
) that metabolizes suxamethonium chloride . As a consequence, the drug’s effect is prolonged, with slower recovery from surgical paralysis. Variation in the
N-acetyltransferaseN-acetyltransferase is an enzyme that catalyzes the transfer of acetyl groups from acetyl-CoA to arylamines. They have wide specificity for aromatic amines, particularly serotonin, and can also catalyze acetyl transfer between arylamines without CoA. EC 2.3.1.5....
gene divides people into “slow acetylators” and “fast acetylators”, with very different half-lives and blood concentrations of such important drugs as
isoniazidIsoniazid is an organic compound that is the first-line antituberculosis medication in prevention and treatment. First discovered in 1912 as an inhibitor of the MAO enzyme, it was first used as an antidepressant, but discontinued due to side effects...
(antituberculosis) and
procainamideProcainamide is a pharmaceutical antiarrhythmic agent used for the medical treatment of cardiac arrhythmias, classified by the Vaughan Williams classification system as class Ia.-Mechanism:...
(antiarrhythmic). As part of the inborn system for clearing the body of
xenobioticA xenobiotic is a chemical which is found in an organism but which is not normally produced or expected to be present in it. It can also cover substances which are present in much higher concentrations than are usual...
s, the
cytochrome P450 oxidaseCytochrome P450 is a very large and diverse superfamily of hemoproteins found in all domains of life. Cytochromes P450 use a plethora of both exogenous and endogenous compounds as substrates in enzymatic reactions...
s (CYPs) are heavily involved in
drug metabolismDrug metabolism is the metabolism of drugs, their biochemical modification or degradation, usually through specialized enzymatic systems. This is a form of xenobiotic metabolism. Drug metabolism often converts lipophilic chemical compounds into more readily excreted polar products...
, and genetic variations in CYPs affect large populations. One member of the CYP superfamily,
CYP2D6Cytochrome P450 2D6 , a member of the cytochrome P450 mixed-function oxidase system, is one of the most important enzymes involved in the metabolism of xenobiotics in the body. Whilst CYP2D6 is involved in the oxidation of a wide range of substrates of all the CYPs, there is considerable...
, now has over 75 known allelic variations, some of which lead to no activity, and some to enhanced activity. An estimated 29% of people in parts of
East AfricaEast Africa or Eastern Africa is the easterly region of the African continent, variably defined by geography or geopolitics. In the UN scheme of geographic regions, 19 territories constitute Eastern Africa:...
may have multiple copies of the gene, and will therefore not be adequately treated with standard doses of drugs such as the painkiller
codeineCodeine or methylmorphine is an opiate used for its analgesic, antitussive, and antidiarrheal properties.-History:Codeine is an alkaloid found in opium and other poppy saps like Papaver bracteatum, the Iranian poppy, in concentrations ranging from 0.3 to 3.0 percent...
(which is activated by the enzyme).
Thiopurines and TPMT (thiopurine methyl transferase)
One of the earliest tests for a genetic variation resulting in a clinically important consequence was on the enzyme
thiopurine methyltransferaseThiopurine methyltransferase or thiopurine S-methyltransferase is an enzyme that methylates thiopurine compounds. The methyl donor is S-adenosyl-L-methionine, which is converted to S-adenosyl-L-homocysteine....
(TPMT). TPMT metabolizes 6-mercaptopurine and
azathioprineAzathioprine is a drug that suppresses the immune system.Azathioprine is used in organ transplantation and autoimmune disease. Some of the autoimmune diseases are rheumatoid arthritis, pemphigus, Inflammatory Bowel Disease , multiple sclerosis, autoimmune hepatitis and restrictive lung...
, two
thiopurineThe thiopurine drugs are purine antimetabolites widely used in the treatment of acute lymphoblastic leukemia, autoimmune disorders and organ transplant recipients.Metabolism is catalyzed by S-methyltransferase....
drugs used in a range of indications, from childhood
leukemiaLeukemia is a cancer of the blood or bone marrow and is characterized by an abnormal proliferation of blood cells, usually white blood cells . Leukemia is a broad term covering a spectrum of diseases...
to autoimmune diseases. In people with a deficiency in TPMT activity, thiopurine metabolism must proceed by other pathways, one of which leads to the active thiopurine
metaboliteMetabolites are the intermediates and products of metabolism. The term metabolite is usually restricted to small molecules. A primary metabolite is directly involved in normal growth, development, and reproduction. A secondary metabolite is not directly involved in those processes, but usually has...
that is toxic to the bone marrow at high concentrations.
Deficiency of TPMT affects a small proportion of people, though seriously. One in 300 people have two variant alleles and lack TPMT activity; these people need only 6-10% of the standard dose of the drug, and, if treated with the full dose, are at risk of severe
bone marrow suppressionBone marrow suppression or myelotoxicity is a serious side-effect of chemotherapy and certain drugs affecting the immune system such as azathioprine...
. For them,
genotypeThe genotype is the genetic constitution of a cell, an organism, or an individual usually with reference to a specific character under consideration...
predicts clinical outcome, a prerequisite for an effective pharmacogenetic test. In 85-90% of affected people, this deficiency results from one of three common variant alleles.
Around 10% of people are heterozygous - they carry one variant allele - and produce a reduced quantity of functional enzyme. Overall, they are at greater risk of adverse effects, although as individuals their
genotypeThe genotype is the genetic constitution of a cell, an organism, or an individual usually with reference to a specific character under consideration...
is not necessarily predictive of their clinical outcome, which makes the interpretation of a clinical test difficult. Recent research suggests that patients who are heterozygous may have a better response to treatment, which raises whether people who have two wild-type alleles could tolerate a higher therapeutic dose.
The US
Food and Drug AdministrationThe Food and Drug Administration is a Government agency of the United States Department of Health and Human Services and is responsible for regulating and supervising the safety of foods, tobacco products, dietary supplements, Medication drugs, vaccines, Biopharmaceutical, blood transfusion,...
(FDA) have recently deliberated the inclusion of a recommendation for testing for TPMT deficiency to the prescribing information for 6-mercaptopurine and
azathioprineAzathioprine is a drug that suppresses the immune system.Azathioprine is used in organ transplantation and autoimmune disease. Some of the autoimmune diseases are rheumatoid arthritis, pemphigus, Inflammatory Bowel Disease , multiple sclerosis, autoimmune hepatitis and restrictive lung...
. Hitherto the information has carried the warning that inherited deficiency of the enzyme could increase the risk of severe bone marrow suppression. Now it will carry the recommendation that people who develop bone marrow suppression while receiving 6-mercaptopurine or azathioprine be tested for TPMT deficiency.
Hepatitis C
A recent breakthrough in pharmacogenetics identified a polymorphism near a human interferon gene that is predictive of the effectiveness of an artificial interferon treatment for Hepatitis C. For genotype 1 hepatitis C treated with Pegylated interferon-alpha-2a or Pegylated interferon-alpha-2b (brand names Pegasys or PEG-Intron) combined with
ribavirinRibavirin is an anti-viral drug indicated for severe RSV infection , hepatitis C infection and other viral infections. Ribavirin is a prodrug, which when metabolised resembles purine RNA nucleotides...
, it has been shown that genetic polymorphisms near the human IL28B gene, encoding interferon lambda 3, are associated with significant differences in response to the treatment. This finding, originally reported in Nature , showed that genotype 1 hepatitis C patients carrying certain genetic variant alleles near the IL28B gene are more possibly to achieve sustained sustained virological response after the treatment than others. Later report from Nature demonstrated that the same genetic variants are also associated with the natural clearance of the genotype 1 hepatitis C virus.
See also
- Genomics
Genomics is the study of the genomes of organisms. The field includes intensive efforts to determine the entire DNA sequence of organisms and fine-scale genetic mapping efforts. The field also includes studies of intragenomic phenomena such as heterosis, epistasis, pleiotropy and other...
- Chemogenomics
Chemogenomics can be defined as the study of genomic responses to chemical compounds. The goal is the rapid identification of novel drugs and drug targets embracing multiple early phase drug discovery technologies ranging from target identification and validation, over compound design and chemical...
- Structural genomics
The aim of structural genomics is the determination of the primary and tertiary structures of all proteins of a given organism, by experimental methods such as X-ray crystallography, NMR spectroscopy or computational approaches such as homology modelling....
- Pharmacogenomics
Pharmacogenomics is the branch of pharmacology which deals with the influence of genetic variation on drug response in patients by correlating gene expression or single-nucleotide polymorphisms with a drug's efficacy or toxicity...
- Toxicogenomics
Toxicogenomics is a field of science that deals with the collection, interpretation, and storage of information about gene and protein activity within particular cell or tissue of an organism in response to toxic substances. Toxicogenomics combines toxicology with genomics or other high throughput...
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