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+#REDIRECT [[Pharmacogenomics]]
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-'''Pharmacogenetics''' is the study of inherited [[genetics|genetic]] differences in drug [[metabolic pathway]]s (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.<ref name="Klotz-2007">{{Cite journal | last1 = Klotz | first1 = U. | title = The role of pharmacogenetics in the metabolism of antiepileptic drugs: pharmacokinetic and therapeutic implications. | journal = Clin Pharmacokinet | volume = 46 | issue = 4 | pages = 271–9 | month =  | year = 2007 | doi =  10.2165/00003088-200746040-00001| pmid = 17375979 }}</ref> 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.<ref>{{cite web| title= Center for Pharmacogenomics and Individualized Therapy| url=https://pharmacy.unc.edu/research/centers/cpit/| accessdate=2017-03-08}}</ref>
-In oncology, ''pharmacogenetics'' historically is the study of [[germline mutation]]s (e.g., [[single-nucleotide polymorphism]]s affecting genes coding for liver enzymes responsible for drug deposition and [[pharmacokinetics]]), whereas ''pharmacogenomics'' refers to [[mutation|somatic mutations]] in [[cancer|tumoral]] DNA leading to alteration in drug response (e.g., [[KRAS]] mutations in patients treated with [[epidermal growth factor receptor|anti-Her1]] [[biologic medical product|biologics]]).<ref name="pmid10866212">{{cite journal | author = Roses AD | title = Pharmacogenetics and the practice of medicine | journal = Nature | volume = 405 | issue = 6788 | pages = 857–65 |date=June 2000 | pmid = 10866212 | doi = 10.1038/35015728 }}</ref> 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.<ref>{{cite journal | vauthors = Syn NL, Yong WP, Lee SC, Goh BC | title = Genetic factors affecting drug disposition in Asian cancer patients | journal = Expert Opinion on Drug Metabolism & Toxicology | volume = 11 | issue = 12 | pages = 1879–92 | date = 2015-01-01 | pmid = 26548636 | doi = 10.1517/17425255.2015.1108964 }}</ref>
-== Predicting drug-drug interactions ==
-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.<ref name="pmid9555760">{{cite journal |vauthors=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 |date=April 1998 | pmid = 9555760 | doi = 10.1001/jama.279.15.1200 }}</ref>{{Unreliable medical source|date=February 2016}} 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.<ref name="Ingelman-Sundberg_2005">{{cite journal |vauthors=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 |date=August 2005 | pmid = 16096104 | pmc = 1569528 | doi = 10.1098/rstb.2005.1685 | url = }}</ref>
-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).
-Scientists and doctors are using this new technology for a variety of things, one being improving the efficacy of drugs. In psychology, we can predict quite accurately which anti-depressant a patient will best respond to by simply looking into their genetic code.{{citation needed|date=September 2013}}{{dubious|date=February 2016|reason=Massively overstates what pharmacogenetics can do - wayyy too confident a claim}} This is a huge step from the previous practice of adjusting and experimenting with different medications to get the best response. Antidepressants also have a large percentage of unresponsive patients and poor prediction rate of ADRs ([[adverse drug reactions]]). In depressed patients, 30% are not helped by [[antidepressant]]s. In psychopharmacological therapy, a patient must be on a drug for 2 weeks before the effects can be fully examined and evaluated. For a patient in that 30%, this could mean months of trying medications to find an antidote to their pain. Any assistance in predicting a patient’s drug reaction to psychopharmacological therapy should be taken advantage of. Pharmacogenetics is a very useful and important tool in predicting which drugs will be effective in various patients.<ref name="pmid20205659">{{cite journal |vauthors=Kirchheiner J, Seeringer A, Viviani R | title = Pharmacogenetics in psychiatry--a useful clinical tool or wishful thinking for the future? | journal = Curr. Pharm. Des. | volume = 16 | issue = 2 | pages = 136–44 | year = 2010 | pmid = 20205659 | doi = 10.2174/138161210790112728}}</ref> 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.<ref name="urlThe 10 Biggest-Selling Drugs That Are About to Lose Their Patent - DailyFinance">{{cite web | url = http://www.dailyfinance.com/2011/02/27/top-selling-drugs-are-about-to-lose-patent-protection-ready/ | title = The 10 Biggest-Selling Drugs That Are About to Lose Their Patent  | author = Alazraki M | year = 2011 | website = | publisher = DailyFinance | pages = | language = | quote = | accessdate = 2012-05-06 }}</ref> [[Genome-wide association study|GWAS]] studies have linked the gene [[CYP2C19]] to those who cannot normally metabolize [[Plavix]]. Plavix is given to patients after receiving a [[Coronary stent|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.<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>
-Another newfound use of pharmacogenetics involves the use of Vitamin E. The Technion Israel Institute of Technology observed that vitamin E can be used to in certain genotypes to lower the risk of cardiovascular disease in patients with [[Diabetes mellitus|diabetes]], but in the same patients with another genotype, vitamin E can raise the risk of cardiovascular disease. A study was carried out, showing vitamin E is able to increase the function of [[High-density lipoprotein|HDL]] in those with the genotype haptoglobin 2-2 who suffer from diabetes. HDL is a lipoprotein that removes cholesterol from the blood and is associated with a reduced risk of atherosclerosis and heart disease. However, if you have the misfortune to possess the genotype haptoglobin 2-1, the study shows that this same treatment can drastically decrease your HDL function and cause cardiovascular disease.<ref name="pmid21722898">{{cite journal |vauthors=Farbstein D, Blum S, Pollak M, Asaf R, Viener HL, Lache O, Asleh R, Miller-Lotan R, Barkay I, Star M, Schwartz A, Kalet-Littman S, Ozeri D, Vaya J, Tavori H, Vardi M, Laor A, Bucher SE, Anbinder Y, Moskovich D, Abbas N, Perry N, Levy Y, Levy AP | title = Vitamin E therapy results in a reduction in HDL function in individuals with diabetes and the haptoglobin 2-1 genotype | journal = Atherosclerosis | volume = 219 | issue = 1 | pages = 240–4 |date=November 2011 | pmid = 21722898 | doi = 10.1016/j.atherosclerosis.2011.06.005 | pmc=3200506}}</ref>
-Pharmacogenetics is a rising concern in clinical oncology, because the therapeutic window of most anticancer drugs is narrow and patients with impaired ability to detoxify drugs will undergo life-threatening toxicities. In particular, genetic deregulations affecting genes coding for [[Dihydropyrimidine dehydrogenase|DPD]], [[UGT1A1]], [[TPMT]], [[cytidine deaminase|CDA]] and [[CYP2D6]] are now considered as critical issues for patients treated with 5-FU/capecitabine, irinotecan, mercaptopurine/azathioprine, gemcitabine/capecitabine/AraC and tamoxifen, respectively. 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. When available, phenotype-based approaches proved their usefulness while being cost-effective.<ref name="pmid20204365">{{cite journal |vauthors=Yang CG, Ciccolini J, Blesius A, Dahan L, Bagarry-Liegey D, Brunet C, Varoquaux A, Frances N, Marouani H, Giovanni A, Ferri-Dessens RM, Chefrour M, Favre R, Duffaud F, Seitz JF, Zanaret M, Lacarelle B, Mercier C | title = DPD-based adaptive dosing of 5-FU in patients with head and neck cancer: impact on treatment efficacy and toxicity | journal = Cancer Chemother. Pharmacol. | volume = 67 | issue = 1 | pages = 49–56 |date=January 2011 | pmid = 20204365 | doi = 10.1007/s00280-010-1282-4  }}</ref>
-In the search for informative correlates of psychotropic drug response, pharmacogenetics has several advantages:<ref>{{cite journal | author = Malhotra AK | year = 2010 | title = The state of pharmacogenetics | url = http://www.psychiatrictimes.com/neuropsychiatry/content/article/10168/1550787 | journal = Psychiatr Times | volume = 27 | issue = 4| pages = 38–41, 62 }}</ref>
-*The genotype of an individual is essentially invariable and remains unaffected by the treatment itself.{{clarify|date=February 2016|reason=This is technically correct in that the genotype is invariable, but the phenotype determined via those genotypes is affected (often quite strongly) by treatment with inhibitors or inducers, and this really needs to be explained. Here's a case of how this plays out: let's say a patient has CYP2D6 genotypes that predict a CYP2D6 phenotype resulting in normal metabolism, but as this hypothetical patient is on fluoxetine (a potent CYP2D6 inhibitor), this result is quite likely not reflective of their actual state of CYP2D6 metabolism (which can be measured directly using dextromethorphan).}}
-*Molecular biology techniques provide an accurate assessment of the genotype of an individual.{{weasel inline|date=February 2016}}
-*There has been a dramatic increase in the amount of genomic information that is available. This information provides the necessary data for comprehensive studies of individual genes and broad investigation of genome-wide variation.
-*The ease of accessibility to genotype information through peripheral blood or saliva sampling and advances in molecular techniques has increased the feasibility of DNA collection and genotyping in large-scale clinical trials.
-==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"/>
-== 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>
-=== Technological advances ===
-As the cost per genetic test decreases, the development of personalized drug therapies will increase.<ref name="pmid17168846">{{cite journal |vauthors=Paul NW, Fangerau H | title = Why should we bother? Ethical and social issues in individualized medicine | journal = Curr Drug Targets | volume = 7 | issue = 12 | pages = 1721–7 |date=December 2006 | pmid = 17168846 | doi = 10.2174/138945006779025428| url = }}</ref> 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]], [https://rxight.com 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.<ref name="isbn0-465-02550-1"/>
-==Ethics==
-Pharmacogenetics has become a controversial issue in the area of [[bioethics]]. It's a new topic to the medical field, as well as the public. This new technique will have a huge impact on society, influencing the treatment of both common and rare diseases. As a new topic in the medical field the ethics behind it are still not clear. However, ethical issues and their possible solutions are already being addressed.
-There are three main ethical issues that have risen from pharmacogenetics. First, would there be a type equity at both drug development and the accessibility to tests.<ref name=Breckenridge>{{cite journal |vauthors=Breckenridge A, Lindpaintner K, Lipton P, McLeod H, Rothstein M, Wallace H | title = Pharmacogenetics: ethical problems and solutions | journal = Nat. Rev. Genet. | volume = 5 | issue = 9 | pages = 676–80 |date=September 2004 | pmid = 15372090 | doi = 10.1038/nrg1431 | url = }}</ref> The concern of accessibility to the test is whether it is going to be available directly to patients via the internet, or over the counter. The second concern regards the confidentiality of storage and usage of genetic information.<ref name=Corrigan>{{cite journal | author = Corrigan OP | title = Pharmacogenetics, ethical issues: review of the Nuffield Council on Bioethics Report | journal = J. Med. Ethics | volume = 31 | issue = 3 | pages = 144–8 |date=March 2005 | pmid = 15738433 | pmc = 1734105 | doi = 10.1136/jme.2004.007229 }}</ref>
-Thirdly, would patients have the control over being tested.
-One concern that has risen is the ethical decision health providers must take with respect to educating the patient of the risks and benefits of medicine developed by this new technology. Pharmacogenetics is a new process that may increase the benefits of medicine while decreasing the risk.  However clinicians have been unsuccessful in educating patients regarding the concept of benefits over risk. The Nuffield Council reported that patients and health professionals have adequate information about pharmacogenetics tests and medicine.<ref name=Corrigan />
-Health care providers will also encounter an ethical decision in deciding to tell their patients that only certain individuals will benefit from the new medicine due to their genetic make-up.<ref name=Breckenridge />  Another ethical concern is that patients who have not taken the test be able to have access to this type of medicine. If access is given by the doctor the medicine could negatively impact the patient's health. The ethical issues behind pharmacogenetics tests, as well as medicine, are still a concern and policies will need to be implemented in the future.
-==See also==
-* [[Chemogenomics]]
-* [[Personalized medicine]]
-* [[Pharmacovigilance]]
-* [[Structural genomics]]
-* [[Toxicogenomics]]
-==References==
-{{Reflist|30em}}
-== 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 |date=October 2003 | pmid = 14574377 | doi = 10.1038/425760a | url = | issn = }}
-* {{cite journal |vauthors=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 |date=February 2003 | pmid = 12571262 | doi = 10.1056/NEJMra020526 | url = | issn = }}
-* {{cite journal |vauthors=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 |date=November 2001 | pmid = 11710893 | doi = 10.1001/jama.286.18.2270| url = | issn = }}
-* {{cite journal | vauthors = Weinshilboum R | title = Inheritance and drug response | journal = The New England Journal of Medicine | volume = 348 | issue = 6 | pages = 529–37 | date = February 2003 | pmid = 12571261 | doi = 10.1056/NEJMra020021 }}
-{{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
-* [https://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
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