Examine individual changes

'{{For|the journal|Pharmacogenetics (journal)}} {{Refimprove|date=May 2007}} 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 [[drug]]s, while [[pharmacogenomics]] is the broader application of genomic technologies to new [[drug 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 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 [[Polymorphism (biology)|polymorphism]]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 [[genotyping]] 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 chloride]], and drugs metabolized by [[N-acetyltransferase]]. One in 3500 [[Caucasian race|Caucasians]] has less efficient variant of the [[enzyme]] ([[butyrylcholinesterase]]) that [[metabolize]]s suxamethonium chloride.<ref name="pmid16968950">{{cite journal | author = Gardiner SJ, Begg EJ | title = Pharmacogenetics, drug-metabolizing enzymes, and clinical practice | journal = Pharmacol. Rev. | volume = 58 | issue = 3 | pages = 521–90 | year = 2006 | month = September | pmid = 16968950 | doi = 10.1124/pr.58.3.6 | url = | issn = }}</ref> 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 [[Mean lifetime|half-lives]] and [[blood concentration]]s of such important drugs as [[isoniazid]] (antituberculosis) and [[procainamide]] (antiarrhythmic). As part of the inborn system for clearing the body of [[xenobiotic]]s, the [[cytochrome P450 oxidase]]s (CYPs) are heavily involved in [[drug metabolism]], and genetic variations in CYPs affect large populations. One member of the CYP 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. ==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 [[ribavirin]], 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,<ref name="pmid19684573">{{cite journal | author = Ge D, Fellay J, Thompson AJ, Simon JS, Shianna KV, Urban TJ, Heinzen EL, Qiu P, Bertelsen AH, Muir AJ, Sulkowski M, McHutchison JG, Goldstein DB | title = Genetic variation in IL28B predicts hepatitis C treatment-induced viral clearance | journal = Nature | volume = 461 | issue = 7262 | pages = 399–401 | year = 2009 | month = September | pmid = 19684573 | doi = 10.1038/nature08309 | url = | issn = }}</ref> 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<ref name="pmid19759533">{{cite journal | author = Thomas DL, Thio CL, Martin MP, Qi Y, Ge D, O'Huigin C, Kidd J, Kidd K, Khakoo SI, Alexander G, Goedert JJ, Kirk GD, Donfield SM, Rosen HR, Tobler LH, Busch MP, McHutchison JG, Goldstein DB, Carrington M | title = Genetic variation in IL28B and spontaneous clearance of hepatitis C virus | journal = Nature | volume = 461 | issue = 7265 | pages = 798–801 | year = 2009 | month = October | pmid = 19759533 | doi = 10.1038/nature08463 | url = | issn = }}</ref> demonstrated that the same genetic variants are also associated with the natural clearance of the genotype 1 hepatitis C virus. ==See also== * [[Genomics]] ** [[Chemogenomics]] ** [[Structural genomics]] ** [[Pharmacogenomics]] ** [[Toxicogenomics]] == References == {{Reflist|2}} == Further reading == {{refbegin|2}} * {{cite journal | author = Abbott A | title = With your genes? Take one of these, three times a day | journal = Nature | volume = 425 | issue = 6960 | pages = 760–2 | year = 2003 | month = October | pmid = 14574377 | doi = 10.1038/425760a | url = | issn = }} * {{cite journal | author = Evans WE, McLeod HL | title = Pharmacogenomics – drug disposition, drug targets, and side effects | journal = N. Engl. J. Med. | volume = 348 | issue = 6 | pages = 538–49 | year = 2003 | month = February | pmid = 12571262 | doi = 10.1056/NEJMra020526 | url = | issn = }} * {{cite journal | author = Ingelman-Sundberg M, Rodriguez-Antona C | title = Pharmacogenetics of drug-metabolizing enzymes: implications for a safer and more effective drug therapy | journal = Philos. Trans. R. Soc. Lond., B, Biol. Sci. | volume = 360 | issue = 1460 | pages = 1563–70 | year = 2005 | month = August | pmid = 16096104 | pmc = 1569528 | doi = 10.1098/rstb.2005.1685 | url = | issn = }} * {{cite journal | author = Lazarou J, Pomeranz BH, Corey PN | title = Incidence of adverse drug reactions in hospitalized patients: a meta-analysis of prospective studies | journal = JAMA | volume = 279 | issue = 15 | pages = 1200–5 | year = 1998 | month = April | pmid = 9555760 | doi = | url = | issn = }} * {{cite journal | author = Phillips KA, Veenstra DL, Oren E, Lee JK, Sadee W | title = Potential role of pharmacogenomics in reducing adverse drug reactions: a systematic review | journal = JAMA | volume = 286 | issue = 18 | pages = 2270–9 | year = 2001 | month = November | pmid = 11710893 | doi = | url = | issn = }} * {{cite journal | author = Weinshilboum R | title = Inheritance and drug response | journal = N. Engl. J. Med. | volume = 348 | issue = 6 | pages = 529–37 | year = 2003 | month = February | pmid = 12571261 | doi = 10.1056/NEJMra020021 | url = | issn = }} {{Refend}} ==External links== *[http://www.ornl.gov/sci/techresources/Human_Genome/medicine/pharma.shtml Pharmacogenomics: Medicine and the new genetics] from the Human Genome Project * [http://www.springer.com/humana+press/pharmacology+and+toxicology/book/978-1-58829-887-4 Pharmacogenomics in Drug Discovery and Development], a book on pharmacogenomics, diseases, personalized medicine, and therapeutics *[http://www.futuremedicine.com The Pharmacogenomics Journal] *[http://www.pharmgkb.org PharmGKB] The Pharmacogenetics and Pharmacogenomics Knowledge Base, a free online tool for Pharmacogenetics research *[http://wikien.pcg-portal.com The pharmacogenetics Wikibase] *[http://www.pgxnews.org PGxNews.Org] - Daily updates about advances in Pharmacogenomics and Personalized Medicine *[http://pharmgenomics.com/index.php?what_is_pharmacogenomics PharmGenomics.com] - Additional information about Pharmacogenomics and Personalized Medicine {{Pharmacology}} {{genomics-footer}} [[Category:Pharmacology|Contents]] [[Category:Pharmacy]] [[ar:صيدلة جينية]] [[cs:Farmakogenetika]] [[de:Pharmakogenetik]] [[fr:Pharmacogénétique]] [[pl:Farmakogenetyka]] [[pt:Farmacogenética]] [[ru:Фармакогенетика]] [[fi:Farmakogenetiikka]][[th:เภสัชพันธุศาสตร์]] [[tr:Farmakogenetik]]'