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Stent clots almost always result in heart attack or sudden death, fortunately it only occurs in 1 or 2% of the population. That 1 or 2% are those with the CYP2C19 SNP.<ref name="pmid19706858">{{cite journal |vauthors=Shuldiner AR, O'Connell JR, Bliden KP, Gandhi A, Ryan K, Horenstein RB, Damcott CM, Pakyz R, Tantry US, Gibson Q, Pollin TI, Post W, Parsa A, Mitchell BD, Faraday N, Herzog W, Gurbel PA | title = Association of cytochrome P450 2C19 genotype with the antiplatelet effect and clinical efficacy of clopidogrel therapy | journal = JAMA | volume = 302 | issue = 8 | pages = 849–57 |date=August 2009 | pmid = 19706858 | doi = 10.1001/jama.2009.1232 | pmc = 3641569 }}</ref> This finding has been applied in at least two hospitals, Scripps and Vanderbilt University, where patients who are candidates for heart stents are screened for the CYP2C19 variants.<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 | location = New York | year = 2012 | pages = | isbn = 978-0-465-02550-3 | oclc = | doi = }}</ref>
Stent clots almost always result in heart attack or sudden death, fortunately it only occurs in 1 or 2% of the population. That 1 or 2% are those with the CYP2C19 SNP.<ref name="pmid19706858">{{cite journal |vauthors=Shuldiner AR, O'Connell JR, Bliden KP, Gandhi A, Ryan K, Horenstein RB, Damcott CM, Pakyz R, Tantry US, Gibson Q, Pollin TI, Post W, Parsa A, Mitchell BD, Faraday N, Herzog W, Gurbel PA | title = Association of cytochrome P450 2C19 genotype with the antiplatelet effect and clinical efficacy of clopidogrel therapy | journal = JAMA | volume = 302 | issue = 8 | pages = 849–57 |date=August 2009 | pmid = 19706858 | doi = 10.1001/jama.2009.1232 | pmc = 3641569 }}</ref> This finding has been applied in at least two hospitals, Scripps and Vanderbilt University, where patients who are candidates for heart stents are screened for the CYP2C19 variants.<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 | location = New York | year = 2012 | pages = | isbn = 978-0-465-02550-3 | oclc = | doi = }}</ref>

In patients with [[type 2 diabetes]], [[haptoglobin]] (Hp) genotyping shows an effect on cardiovascular disease, with Hp2-2 at higher risk and supplemental vitamin E reducing risk by affecting [[High-density lipoprotein|HDL]].<ref>{{Cite journal|last=Vigerust|first=David J.|last2=Doneen|first2=Amy L.|last3=Bale|first3=Bradley F.|date=2018|title=Precision Healthcare of Type 2 Diabetic Patients Through Implementation of Haptoglobin Genotyping|url=https://www.frontiersin.org/articles/10.3389/fcvm.2018.00141/full?&u|journal=Frontiers in Cardiovascular Medicine|language=English|volume=5|doi=10.3389/fcvm.2018.00141|issn=2297-055X}}</ref>


==History==
==History==

Revision as of 20:01, 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]

Predicting drug-drug interactions

Pharmacogenetics is a very useful and important tool in predicting which drugs will be effective in various patients.[5] The drug Plavix blocks platelet reception and is the second best selling prescription drug in the world, however, it is known to warrant different responses among patients.[6] GWAS studies have linked the gene CYP2C19 to those who cannot normally metabolize Plavix. Plavix is given to patients after receiving a stent in the coronary artery to prevent clotting.

Stent clots almost always result in heart attack or sudden death, fortunately it only occurs in 1 or 2% of the population. That 1 or 2% are those with the CYP2C19 SNP.[7] This finding has been applied in at least two hospitals, Scripps and Vanderbilt University, where patients who are candidates for heart stents are screened for the CYP2C19 variants.[8]

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.[9] 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.[8]

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.[10] 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. [11]

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 polymorphisms, which could help in a situation such as being a patient in the emergency room.[12] As pharmacogenetics continues to gain acceptance in clinical practice, when to utilize pharmacogenetics will be of importance in advancing patient care.[13]

Technological advances

As the cost per genetic test decreases, the development of personalized drug therapies will increase.[14] 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, MD Labs Pharmacogenetics, Navigenics and 23andMe offer genome scans. The companies use the same genotyping 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.[8]

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. ^ Kirchheiner J, Seeringer A, Viviani R (2010). "Pharmacogenetics in psychiatry--a useful clinical tool or wishful thinking for the future?". Curr. Pharm. Des. 16 (2): 136–44. doi:10.2174/138161210790112728. PMID 20205659.
  6. ^ Alazraki M (2011). "The 10 Biggest-Selling Drugs That Are About to Lose Their Patent". DailyFinance. Retrieved 2012-05-06.
  7. ^ Shuldiner AR, O'Connell JR, Bliden KP, Gandhi A, Ryan K, Horenstein RB, Damcott CM, Pakyz R, Tantry US, Gibson Q, Pollin TI, Post W, Parsa A, Mitchell BD, Faraday N, Herzog W, Gurbel PA (August 2009). "Association of cytochrome P450 2C19 genotype with the antiplatelet effect and clinical efficacy of clopidogrel therapy". JAMA. 302 (8): 849–57. doi:10.1001/jama.2009.1232. PMC 3641569. PMID 19706858.
  8. ^ a b c 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.
  9. ^ 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.
  10. ^ Frueh FW, Amur S, Mummaneni P, Epstein RS, Aubert RE, DeLuca TM, Verbrugge RR, Burckart GJ, Lesko LJ (August 2008). "Pharmacogenomic biomarker information in drug labels approved by the United States food and drug administration: prevalence of related drug use". Pharmacotherapy. 28 (8): 992–8. doi:10.1592/phco.28.8.992. PMID 18657016.
  11. ^ Corrigan OP (2011). "Personalized Medicine in a Consumer Age". Current Pharmacogenomics and Personalized Medicine. 9 (3): 168–176. doi:10.2174/187569211796957566.
  12. ^ Director, Dr Soram Khalsa Medical; Institute, East-West Medical Research (2015-06-28). "Pharmacogenetics: What It Is And Why You Need to Know". The Huffington Post. Retrieved 2016-10-05.
  13. ^ Alzghari SK, Blakeney L, Rambaran KA (May 2017). "Proposal for a Pharmacogenetic Decision Algorithm". Cureus. 9 (5): e1289. doi:10.7759/cureus.1289. PMC 5493454. PMID 28680777.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  14. ^ Paul NW, Fangerau H (December 2006). "Why should we bother? Ethical and social issues in individualized medicine". Curr Drug Targets. 7 (12): 1721–7. doi:10.2174/138945006779025428. PMID 17168846.

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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