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Cytochrome P450 2C19
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'''Cytochrome P450 2C19''' or '''Cytochrome P450 Family 2 Subfamily C Member 19''' or '''CYP2C19''' is a gene linked to drug metabolism. Variants in CYP2C19 or lack of the gene are extremely common, with one study finding that over 50% of people in the study had either no CYP2C19 gene or a variant of it.<ref name="Ionova2020" /> ==Function== Variants in CYP2C19 or the absence of the gene can significantly alter the drug metabolism of several medications, genotype‐based dosing guidelines available for these medications.<ref name="Ionova2020">{{Cite journal | last = Ionova | first = Yelena | authorlink = | last2 = Ashenhurst | first2 = James | authorlink2 = | last3 = Zhan | first3 = Jianan | author-link3 = | last4 = Nhan | first4 = Hoang | author-link4 = | last5 = Kosinski | first5 = Cindy | author-link5 = | last6 = Tamraz | first6 = Bani | author-link6 = | last7 = Chubb | first7 = Alison | date = 2020 | title=CYP2C19 Allele Frequencies in Over 2.2 Million Direct-to-Consumer Genetics Research Participants and the Potential Implication for Prescriptions in a Large Health System | url = https://ascpt.onlinelibrary.wiley.com/doi/abs/10.1111/cts.12830|journal=Clinical and Translational Science|language=en|volume=13|issue=6 | pages = 1298–1306|doi=10.1111/cts.12830|issn=1752-8062|pmc=7719394|pmid=32506666|access-date=|quote=|via=}}</ref> ==Drug responses == CYP2C19 variants are known to affect the metabolism of the [[tricyclic antidepressant]]s [[amitriptyline]], [[clomipramine]], [[doxepin]] and [[imipramine]], the [[selective serotonin reuptake inhibitor]]s (SSRIs) [[citalopram]] and [[sertraline]], the antifungal drug voriconazole, and the antiplatelet agent clopidogrel which reduces blood clotting.<ref name="Petrovic2019">{{Cite journal | last = Petrović|first = Jelena | authorlink = | last2 = Pešić | first2 = Vesna | authorlink2 = | last3 = Lauschke | first3 = Volker M. | author-link3 = | date = Jan 2020 | title = Frequencies of clinically important CYP2C19 and CYP2D6 alleles are graded across Europe | url =https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6906321/|journal=European Journal of Human Genetics|volume=28|issue=1 | pages = 88–94|doi=10.1038/s41431-019-0480-8|issn=1018-4813|pmc=6906321|pmid=31358955|access-date=|quote=|via=}}</ref> An FDA warning was been added to clopidogrel in 2009 which started that genetic testing was available to determine if a patient could be a poor metabolizer, and that this would make the drug less effective.<ref name="FDA2009">{{Cite journal | last = Center for Drug Evaluation and Research|first = | authorlink = | date = 2019-06-28 | title = FDA Drug Safety Communication: Reduced effectiveness of Plavix (clopidogrel) in patients who are poor metabolizers of the drug | url =https://www.fda.gov/drugs/postmarket-drug-safety-information-patients-and-providers/fda-drug-safety-communication-reduced-effectiveness-plavix-clopidogrel-patients-who-are-poor|journal=FDA|language=en|volume=|issue=| pages=|doi=|pmc=|pmid=|access-date=|quote=|via=}}</ref> ==Variants == *'''rs12248560''' (CYP2C19*17) ultrarapid CYP2C19 metabolism and increases increases enzyme function, acting in the opposite way to rs4244285. In Europe, this variant affects between 1 in 3 and 1 in 9 people.<ref name="Petrovic2019" /> *'''rs4244285''' (CYP2C19*2) is the most common variant in Caucasians, and results in aberrant splicing and loss of function, rs12248560 acts in the opposite way. This variant also affects around 1 in 5 people in the Romany (traveler) community in one study.<ref name="Petrovic2019" /> If combined with the CYP2C19*1 normal functioning variant drug effectiveness improves compared to having two copies of rs4244285.<ref name="FDA2009" /> * (CYP2C19*1) normal functioning<ref name="FDA2009" /> *'''rs17885098''' (CYP2C19*1B) normal function<ref name="PharmVar">{{Cite web | url = https://www.pharmvar.org/htdocs/archive/cyp2c19.htm | title = CYP2C19 | last = | first = | authorlink = | date = | website = PharmVar Archive| archive-url = | archive-date = |url-status = | access-date=2021-04-07}}</ref> *'''rs3758581''' (CYP2C19*1C, CYP2C19*3C, CYP2C19*4A, CYP2C19*4B and many others) 991A>G normal functioning, some others cause loss of function<ref name="PharmVar" /> *'''rs4986893''' (CYP2C19*3, CYP2C19*3A, CYP2C19*3B, CYP2C19*3C 636 G>A) <ref name="Hulot2006">{{Cite journal | date = 2006-10-01 | title = Cytochrome P450 2C19 loss-of-function polymorphism is a major determinant of clopidogrel responsiveness in healthy subjects |url =https://www.sciencedirect.com/science/article/pii/S0006497120525056|journal=Blood|language=en|volume=108|issue=7 | pages = 2244–2247|doi=10.1182/blood-2006-04-013052|issn=0006-4971}}</ref> *'''rs3758581''' (CYP2C19*3A) loss of function<ref name="PharmVar" /> *'''rs17886522''' (CYP2C19*3B or CYP2C19*20) loss of function<ref name="PharmVar" /> *'''rs3758581''' (CYP2C19*3B or CYP2C19*20, CYP2C19*3C) loss of function<ref name="PharmVar" /> *'''rs144036596''' (CYP2C19*3B or CYP2C19*20) loss of function<ref name="PharmVar" /> *'''rs4986893''' (CYP2C19*3B or CYP2C19*20) loss of function<ref name="PharmVar" /> *'''rs397516695''' (CYP2C19*3C) 407T>A<ref name="rs397516695">{{Cite web | url = https://www.ncbi.nlm.nih.gov/snp/rs397516695 | title = rs397516695 RefSNP Report - dbSNP - Short Genetic Variations | last = | first = | authorlink = | date = | website = NCBI| archive-url = | archive-date = |url-status = | access-date=2022-03-31}}</ref><ref name="PharmVar" /> *'''rs17886522''' (CYP2C19*3C) 1251A>C<ref name="rs17886522">{{Cite web | url = https://www.ncbi.nlm.nih.gov/snp/rs17886522 | title = rs17886522 RefSNP Report - dbSNP - Short Genetic Variations | last = | first = | authorlink = | date = | website = NCBI| archive-url = | archive-date = |url-status = | access-date=2022-03-31}}</ref><ref name="PharmVar" /> *'''rs28399504''' (CYP2C19*4) A>G<ref name="Hulot2006" /> *'''rs unknown''' (CYP2C19*5) 1297 C>T <ref name="Hulot2006" /> *'''rs unknown''' (CYP2C19*6)<ref name="Hulot2006" /> Conflicting data in different studies make it unclear which areas of European are most affected by these variants.<ref name="FDA2009" /> ===Variant combinations === {| class="wikitable" |- ! Likely effect !! Combination |- | Ultrarapid metabolizer: normal or increased activity (~5–30% of patients) || Two increased activity alleles (*17) or one functional allele (*1) plus one increased-activity allele (*17), eg and rs12248560. |- | Extensive metabolizer: homozygous wild-type or normal activity (~35–50% of patients) || Two functional (*1) alleles e.g. |- | Intermediate metabolizer: heterozygote or intermediate activity (~18–45% of patients) || <!-- Example --> |- | Poor metabolizer: homozygous variant, mutant, low, or deficient activity (~2–15% of patients) || <!-- Example--> <ref name="Scott2013">{{Cite journal | last = Scott | first = S.A. | last2 = Sangkuhl | first2 = K. | last3 = Stein | first3 = C.M. | last4 = Hulot | first4 = J.-S. | last5 = Mega | first5 = J.L. | last6 = Roden | first6 = D.M. | last7 = Klein | first7 = T.E. | last8 = Sabatine | first8 = M.S. | last9 = Johnson | first9 = J.A. | date = 2013 | title = Clinical Pharmacogenetics Implementation Consortium Guidelines for CYP2C19 Genotype and Clopidogrel Therapy: 2013 Update | url =https://ascpt.onlinelibrary.wiley.com/doi/abs/10.1038/clpt.2013.105|journal=Clinical Pharmacology & Therapeutics|language=en|volume=94|issue=3 | pages = 317–323|doi=10.1038/clpt.2013.105|issn=1532-6535|pmc=3748366|pmid=23698643}}</ref> |} ==CYP2D6== Common variants of [[cytochrome P450 2D6]] (CYP2D6) also impact the effects of these drugs. {{See also|1=Cytochrome P450 2D6|2=CYP2D6}} ==ME/CFS== No particular link to [[ME/CFS]] has been found for people with CYP2C19 gene variants. One study found CYP2C19 to be one of a number of genes associated with [[multiple chemical sensitivity]], but other studies failed to find this.<ref name="Ionova2020" /> ==See also== * [[Cytochrome P450 2D6|CYP2D6]] ==Learn more== *[https://www.genecards.org/cgi-bin/carddisp.pl?gene=CYP2C19 CYP2C19] - Gene cards *[https://www.pharmvar.org/htdocs/archive/cyp2c19.htm CYP2C19 variants] - PharmVar archive ==References== {{reflist}} [[Category:Genes]]
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