Phenytoin is an antiepileptic drug with a narrow therapeutic index and large interpatient pharmacokinetic variability, partly due to genetic variation in CYP2C9. Furthermore, the variant allele ...HLA‐B*15:02 is associated with an increased risk of Stevens–Johnson syndrome and toxic epidermal necrolysis in response to phenytoin treatment. We summarize evidence from the published literature supporting these associations and provide therapeutic recommendations for the use of phenytoin based on CYP2C9 and/or HLA‐B genotypes (updates on cpicpgx.org).
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Pharmacogenetics (PGx) studies the influence of genetic variation on drug response. Clinically actionable associations inform guidelines created by the Clinical Pharmacogenetics Implementation ...Consortium (CPIC), but the broad impact of genetic variation on entire populations is not well understood. We analyzed PGx allele and phenotype frequencies for 487,409 participants in the UK Biobank, the largest PGx study to date. For 14 CPIC pharmacogenes known to influence human drug response, we find that 99.5% of individuals may have an atypical response to at least 1 drug; on average they may have an atypical response to 10.3 drugs. Nearly 24% of participants have been prescribed a drug for which they are predicted to have an atypical response. Non‐European populations carry a greater frequency of variants that are predicted to be functionally deleterious; many of these are not captured by current PGx allele definitions. Strategies for detecting and interpreting rare variation will be critical for enabling broad application of pharmacogenetics.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Clinicians are encouraged to document the reasons for the use of a particular procedure or test, whether or not it is in conformance with this statement. Clinicians also are advised to take notice of ...the date this statement was adopted, and to consider other medical and scientific information that becomes available after that date. It also would be prudent to consider whether intellectual property interests may restrict the performance of certain tests and other procedures. Where individual authors are listed, the views expressed may not reflect those of authors’ employers or affiliated institutions.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Nonsteroidal anti‐inflammatory drugs (NSAIDs) are among the most commonly used analgesics due to their lack of addictive potential. However, NSAIDs have the potential to cause serious ...gastrointestinal, renal, and cardiovascular adverse events. CYP2C9 polymorphisms influence metabolism and clearance of several drugs in this class, thereby affecting drug exposure and potentially safety. We summarize evidence from the published literature supporting these associations and provide therapeutic recommendations for NSAIDs based on CYP2C9 genotype (updates at www.cpicpgx.org).
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Personalized medicine is expected to benefit from combining genomic information with regular monitoring of physiological states by multiple high-throughput methods. Here, we present an integrative ...personal omics profile (iPOP), an analysis that combines genomic, transcriptomic, proteomic, metabolomic, and autoantibody profiles from a single individual over a 14 month period. Our iPOP analysis revealed various medical risks, including type 2 diabetes. It also uncovered extensive, dynamic changes in diverse molecular components and biological pathways across healthy and diseased conditions. Extremely high-coverage genomic and transcriptomic data, which provide the basis of our iPOP, revealed extensive heteroallelic changes during healthy and diseased states and an unexpected RNA editing mechanism. This study demonstrates that longitudinal iPOP can be used to interpret healthy and diseased states by connecting genomic information with additional dynamic omics activity.
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► Physiological states analyzed by integrative personal omics profiling ► Extensive molecular changes revealed during different health states ► Individual disease risk predicted from integrated omics data ► Extensive heteroallele and RNA editing during healthy and disease states
A personalized medicine pilot study samples a patient's transcriptome, proteome, and metabolome multiple times over the course of 14 months and integrates this information with whole-genome sequence data to predict risk and provide a comprehensive view of healthy and disease states, including two viral infections and the onset of type 2 diabetes.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Since whole-genome sequencing will show that every patient has an above-average risk for some disorders, and for having children with some genetic diseases, every patient could face some negative ...social consequences from those risks, whether in insurance, employment, stigma, or otherwise. ... specific sequencing methods will have limitations that need to be understood. ... interpretation of a whole-genome sequence requires good information about every known genetic disease and pharmacological risk.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
CYP2C19 catalyzes the bioactivation of the antiplatelet prodrug clopidogrel, and CYP2C19 genotype impacts clopidogrel active metabolite formation. CYP2C19 intermediate and poor metabolizers who ...receive clopidogrel experience reduced platelet inhibition and increased risk for major adverse cardiovascular and cerebrovascular events. This guideline is an update to the 2013 Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for the use of clopidogrel based on CYP2C19 genotype and includes expanded indications for CYP2C19 genotype‐guided antiplatelet therapy, increased strength of recommendation for CYP2C19 intermediate metabolizers, updated CYP2C19 genotype to phenotype translation, and evidence from an expanded literature review (updates at www.cpicpgx.org).
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
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