Pharmacogenetics

Overview
The terms pharmacogenomics 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 variation that gives rise to differing response to drugs, while pharmacogenomics is the broader application of genomic technologies to new drug discovery and further characterization of older drugs. Pharmacogenetics considers one or at most a few genes of interest, while pharmacogenomics considers the entire genome.

Pharmacogenetics and adverse drug reactions
Much of current clinical interest is at the level of pharmacogenetics, involving variation in genes involved in, drug metabolism 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 polymorphisms found that drugs commonly involved in adverse drug reactions were also those that were metabolized by enzymes with known polymorphisms (see Phillips, 2001).

History
The first observations of genetic variation in drug response date from the 1950s, involving the muscle relaxant suxamethonium chloride, and drugs metabolized by N-acetyltransferase. One in 3500 Caucasians has less efficient variant of the enzyme (butyrylcholinesterase) that metabolizes suxamethonium chloride. As a consequence, the drug’s effect is prolonged, with slower recovery from surgical paralysis. Variation in the N-acetyltransferase gene divides people into “slow acetylators” and “fast acetylators”, with very different half-lives and blood concentrations of such important drugs as isoniazid (antituberculosis) and procainamide (antiarrhythmic). As part of the inborn system for clearing the body of xenobiotics, the cytochrome P450 oxidases (CYP450) are heavily involved in drug metabolism, and genetic variations in CYP450s affect large populations. One member of the CYP450 superfamily, CYP2D6, 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 Africa may have multiple copies of the gene, and will therefore not be adequately treated with standard doses of drugs such as the painkiller codeine (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 methyltransferase (TPMT). TPMT metabolizes 6-mercaptopurine and azathioprine, two thiopurine drugs used in a range of indications, from childhood leukemia 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 metabolite 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 suppression. For them, genotype 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 genotype 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 Administration (FDA) have recently deliberated the inclusion of a recommendation for testing for TPMT deficiency to the prescribing information for 6-mercaptopurine and azathioprine. 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.