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==History==
==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 |vauthors=Gardiner SJ, Begg EJ | title = Pharmacogenetics, drug-metabolizing enzymes, and clinical practice | journal = Pharmacol. Rev. | volume = 58 | issue = 3 | pages = 521–90 |date=September 2006 | 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). The first study using Genome-wide association studies (GWAS) linked age-related macular degeneration (AMD) with a SNP located on chromosome 1 that increased one’s risk of AMD. AMD is the most common cause of blindness, affecting more than seven million Americans. Until this study in 2005, we only knew about the inflammation of the retinal tissue causing AMD, not the genes responsible.<ref name="isbn0-465-02550-1">{{cite book|title=The Creative Destruction of Medicine: How the Digital Revolution Will Create Better Health Care|publisher=Basic Books|year=2012|isbn=978-0-465-02550-3|location=New York|pages=|doi=|oclc=}}</ref>
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 |vauthors=Gardiner SJ, Begg EJ | title = Pharmacogenetics, drug-metabolizing enzymes, and clinical practice | journal = Pharmacol. Rev. | volume = 58 | issue = 3 | pages = 521–90 |date=September 2006 | 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). The first study using Genome-wide association studies (GWAS) linked age-related macular degeneration (AMD) with a SNP located on chromosome 1 that increased one’s risk of AMD. AMD is the most common cause of blindness, affecting more than seven million Americans. Until this study in 2005, we only knew about the inflammation of the retinal tissue causing AMD, not the genes responsible.<ref name="isbn0-465-02550-1">{{cite book|title=The Creative Destruction of Medicine: How the Digital Revolution Will Create Better Health Care|publisher=Basic Books|year=2012|isbn=978-0-465-02550-3|location=New York|pages=|doi=|oclc=}}</ref>

== Integrating into the health care system ==

Despite the many successes, most drugs are not tested using GWAS. However, it is estimated that over 25% of common medication have some type of genetic information that could be used in the medical field.<ref name="pmid18657016">{{cite journal |vauthors=Frueh FW, Amur S, Mummaneni P, Epstein RS, Aubert RE, DeLuca TM, Verbrugge RR, Burckart GJ, Lesko LJ | title = Pharmacogenomic biomarker information in drug labels approved by the United States food and drug administration: prevalence of related drug use | journal = Pharmacotherapy | volume = 28 | issue = 8 | pages = 992–8 |date=August 2008 | pmid = 18657016 | doi = 10.1592/phco.28.8.992 }}</ref> If the use of [[personalized medicine]] is widely adopted and used, it will make medical trials more efficient. This will lower the costs that come about due to adverse drug side effects and prescription of drugs that have been proven ineffective in certain genotypes. It is very costly when a clinical trial is put to a stop by licensing authorities because of the small population who experiences adverse drug reactions. With the new push for pharmacogenetics, it is possible to develop and license a drug specifically intended for those who are the small population genetically at risk for adverse side effects.
<ref name=Corrigan_2010>{{cite journal | author = Corrigan OP | title = Personalized Medicine in a Consumer Age|journal=Current Pharmacogenomics and Personalized Medicine |volume= 9 | issue = 3| pages = 168–176 | year = 2011 | doi = 10.2174/187569211796957566 }}</ref>

The ability to test and analyze an individual’s DNA to determine if the body can break down certain drugs through the biochemical pathways has application in all fields of medicine. Pharmacogenetics gives those in the health care industry a potential solution to help prevent the significant number of deaths that occur each year due to drug reactions and side effects. The companies or laboratories that perform this testing can do so across all categories or drugs whether it be for high blood pressure, gastrointestinal, urological, psychotropic or anti-anxiety drugs. Results can be presented showing which drugs the body is capable of breaking down normally versus the drugs the body cannot break down normally. This test only needs to be done once and can provide valuable information such as a summary of an individual’s genetic [[Single-nucleotide polymorphism|polymorphisms]], which could help in a situation such as being a patient in the emergency room.<ref>{{cite web|url=http://www.huffingtonpost.com/dr-soram-khalsa/pharmacogenetics-what-it-is-_b_7683164.html|title=Pharmacogenetics: What It Is And Why You Need to Know|last=Director|first=Dr Soram Khalsa Medical|last2=Institute|first2=East-West Medical Research|date=2015-06-28|website=The Huffington Post|access-date=2016-10-05}}</ref> As pharmacogenetics continues to gain acceptance in clinical practice, when to utilize pharmacogenetics will be of importance in advancing patient care.<ref>{{cite journal | vauthors = Alzghari SK, Blakeney L, Rambaran KA | title = Proposal for a Pharmacogenetic Decision Algorithm | journal = Cureus | volume = 9 | issue = 5 | pages = e1289 | date = May 2017 | pmid = 28680777 | pmc = 5493454 | doi = 10.7759/cureus.1289 }}</ref>


==See also==
==See also==

Revision as of 20:30, 17 June 2019

Pharmacogenetics is the study of inherited genetic differences in drug metabolic pathways (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.[1] The term pharmacogenetics is often used interchangeably with the term pharmacogenomics which also investigates the role of acquired and inherited genetic differences in relation to drug response and drug behaviour through a systematic examination of genes, gene products, and inter- and intra-individual variation in gene expression and function.[2]

In oncology, pharmacogenetics historically is the study of germline mutations (e.g., single-nucleotide polymorphisms affecting genes coding for liver enzymes responsible for drug deposition and pharmacokinetics), whereas pharmacogenomics refers to somatic mutations in tumoral DNA leading to alteration in drug response (e.g., KRAS mutations in patients treated with anti-Her1 biologics).[3] Pharmacogenetics is believed to account for inter-ethnic differences (e.g., between patients of Asian, Caucasian and African descent) in adverse events and efficacy profiles of many widely used drugs in cancer chemotherapy.[4]

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.[5] 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 (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). The first study using Genome-wide association studies (GWAS) linked age-related macular degeneration (AMD) with a SNP located on chromosome 1 that increased one’s risk of AMD. AMD is the most common cause of blindness, affecting more than seven million Americans. Until this study in 2005, we only knew about the inflammation of the retinal tissue causing AMD, not the genes responsible.[6]

See also

References

  1. ^ Klotz, U. (2007). "The role of pharmacogenetics in the metabolism of antiepileptic drugs: pharmacokinetic and therapeutic implications". Clin Pharmacokinet. 46 (4): 271–9. doi:10.2165/00003088-200746040-00001. PMID 17375979. {{cite journal}}: Cite has empty unknown parameter: |month= (help)
  2. ^ "Center for Pharmacogenomics and Individualized Therapy". Retrieved 2017-03-08.
  3. ^ Roses AD (June 2000). "Pharmacogenetics and the practice of medicine". Nature. 405 (6788): 857–65. doi:10.1038/35015728. PMID 10866212.
  4. ^ Syn NL, Yong WP, Lee SC, Goh BC (2015-01-01). "Genetic factors affecting drug disposition in Asian cancer patients". Expert Opinion on Drug Metabolism & Toxicology. 11 (12): 1879–92. doi:10.1517/17425255.2015.1108964. PMID 26548636.
  5. ^ Gardiner SJ, Begg EJ (September 2006). "Pharmacogenetics, drug-metabolizing enzymes, and clinical practice". Pharmacol. Rev. 58 (3): 521–90. doi:10.1124/pr.58.3.6. PMID 16968950.
  6. ^ The Creative Destruction of Medicine: How the Digital Revolution Will Create Better Health Care. New York: Basic Books. 2012. ISBN 978-0-465-02550-3.

Further reading

  • Abbott A (October 2003). "With your genes? Take one of these, three times a day". Nature. 425 (6960): 760–2. doi:10.1038/425760a. PMID 14574377.
  • Evans WE, McLeod HL (February 2003). "Pharmacogenomics – drug disposition, drug targets, and side effects". N. Engl. J. Med. 348 (6): 538–49. doi:10.1056/NEJMra020526. PMID 12571262.
  • Phillips KA, Veenstra DL, Oren E, Lee JK, Sadee W (November 2001). "Potential role of pharmacogenomics in reducing adverse drug reactions: a systematic review". JAMA. 286 (18): 2270–9. doi:10.1001/jama.286.18.2270. PMID 11710893.
  • Weinshilboum R (February 2003). "Inheritance and drug response". The New England Journal of Medicine. 348 (6): 529–37. doi:10.1056/NEJMra020021. PMID 12571261.
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