Subject(s)
Mental Disorders/drug therapy , Selective Serotonin Reuptake Inhibitors/pharmacokinetics , Sertraline/pharmacokinetics , Drug Interactions , Humans , Pharmacogenomic Variants , Selective Serotonin Reuptake Inhibitors/adverse effects , Selective Serotonin Reuptake Inhibitors/pharmacology , Sertraline/adverse effects , Sertraline/pharmacology , Signal Transduction/drug effectsABSTRACT
Genome editing tools enable efficient and accurate genome manipulation. An enhanced ability to modify the genomes of livestock species could be utilized to improve disease resistance, productivity or breeding capability as well as the generation of new biomedical models. To date, with respect to the direct injection of genome editor mRNA into livestock zygotes, this technology has been limited to the generation of pigs with edited genomes. To capture the far-reaching applications of gene-editing, from disease modelling to agricultural improvement, the technology must be easily applied to a number of species using a variety of approaches. In this study, we demonstrate zygote injection of TALEN mRNA can also produce gene-edited cattle and sheep. In both species we have targeted the myostatin (MSTN) gene. In addition, we report a critical innovation for application of gene-editing to the cattle industry whereby gene-edited calves can be produced with specified genetics by ovum pickup, in vitro fertilization and zygote microinjection (OPU-IVF-ZM). This provides a practical alternative to somatic cell nuclear transfer for gene knockout or introgression of desirable alleles into a target breed/genetic line.
Subject(s)
Animals, Genetically Modified/genetics , Genome , Myostatin/genetics , Sheep, Domestic/genetics , Animals , Breeding , Cattle , Fertilization in Vitro , Genetic Engineering , Livestock , Nuclear Transfer Techniques , ZygoteSubject(s)
Cytochrome P-450 CYP2D6/genetics , Metabolic Networks and Pathways/drug effects , Ondansetron/pharmacokinetics , Tropisetron/pharmacokinetics , Cytochrome P-450 CYP1A2/genetics , Cytochrome P-450 CYP2D6/metabolism , Humans , Inactivation, Metabolic/genetics , Ondansetron/metabolism , Ondansetron/therapeutic use , Receptors, Serotonin, 5-HT3/genetics , Receptors, Serotonin, 5-HT3/metabolism , Serotonin/metabolism , Serotonin Antagonists/metabolism , Serotonin Antagonists/pharmacokinetics , Serotonin Antagonists/therapeutic use , Tropisetron/metabolism , Tropisetron/therapeutic useABSTRACT
Beta-blockers are widely used medications for a variety of indications, including heart failure, myocardial infarction, cardiac arrhythmias, and hypertension. Genetic variability in pharmacokinetic (e.g., CYP2D6) and pharmacodynamic (e.g., ADRB1, ADRB2, ADRA2C, GRK4, GRK5) genes have been studied in relation to beta-blocker exposure and response. We searched and summarized the strength of the evidence linking beta-blocker exposure and response with the six genes listed above. The level of evidence was high for associations between CYP2D6 genetic variation and both metoprolol exposure and heart rate response. Evidence indicates that CYP2D6 poor metabolizers experience clinically significant greater exposure and lower heart rate in response to metoprolol compared with those who are not poor metabolizers. Therefore, we provide therapeutic recommendations regarding genetically predicted CYP2D6 metabolizer status and metoprolol therapy. However, there was insufficient evidence to make therapeutic recommendations for CYP2D6 and other beta-blockers or for any beta-blocker and the other five genes evaluated (updates at www.cpicpgx.org).
Subject(s)
Anticonvulsants/therapeutic use , Benzodiazepines/therapeutic use , Clobazam/chemistry , Clobazam/therapeutic use , Anticonvulsants/chemistry , Anticonvulsants/pharmacokinetics , Benzodiazepines/chemistry , Benzodiazepines/pharmacokinetics , Clobazam/pharmacokinetics , Humans , PharmacogeneticsABSTRACT
Aminoglycosides are widely used antibiotics with notable side effects, such as nephrotoxicity, vestibulotoxicity, and sensorineural hearing loss (cochleotoxicity). MT-RNR1 is a gene that encodes the 12s rRNA subunit and is the mitochondrial homologue of the prokaryotic 16s rRNA. Some MT-RNR1 variants (i.e., m.1095T>C; m.1494C>T; m.1555A>G) more closely resemble the bacterial 16s rRNA subunit and result in increased risk of aminoglycoside-induced hearing loss. Use of aminoglycosides should be avoided in individuals with an MT-RNR1 variant associated with an increased risk of aminoglycoside-induced hearing loss unless the high risk of permanent hearing loss is outweighed by the severity of infection and safe or effective alternative therapies are not available. We summarize evidence from the literature supporting this association and provide therapeutic recommendations for the use of aminoglycosides based on MT-RNR1 genotype (updates at https://cpicpgx.org/guidelines/ and www.pharmgkb.org).
Subject(s)
Aminoglycosides/adverse effects , Anti-Bacterial Agents/adverse effects , Hearing Loss, Sensorineural/chemically induced , Hearing Loss, Sensorineural/genetics , Pharmacogenomic Variants , RNA, Ribosomal/genetics , Clinical Decision-Making , Genotype , Hearing Loss, Sensorineural/diagnosis , Humans , Ototoxicity , Patient Safety , Pharmacogenetics , Pharmacogenomic Testing , Predictive Value of Tests , Risk Assessment , Risk FactorsABSTRACT
Pharmacogenomics (PGx) is a key area of precision medicine, which is already being implemented in some health systems and may help guide clinicians toward effective therapies for individual patients. Over the last 2 decades, the Pharmacogenomics Knowledgebase (PharmGKB) has built a unique repository of PGx knowledge, including annotations of clinical guideline and regulator-approved drug labels in addition to evidence-based drug pathways and annotations of the scientific literature. All of this knowledge is freely accessible on the PharmGKB website. In the first of a series of PharmGKB tutorials, we introduce the PharmGKB coronavirus disease 2019 (COVID-19) portal and, using examples of drugs found in the portal, demonstrate some of the main features of PharmGKB. This paper is intended as a resource to help users become quickly acquainted with the wealth of information stored in PharmGKB.
Subject(s)
Antiviral Agents/pharmacokinetics , COVID-19 Drug Treatment , COVID-19 , Gene Ontology , Knowledge Bases , Pharmacogenetics , Pharmacogenomic Testing/methods , COVID-19/genetics , Humans , Medication Therapy Management , Pharmacogenetics/education , Pharmacogenetics/methods , Precision Medicine/methodsABSTRACT
Clinical annotations are one of the most popular resources available on the Pharmacogenomics Knowledgebase (PharmGKB). Each clinical annotation summarizes the association between variant-drug pairs, shows relevant findings from the curated literature, and is assigned a level of evidence (LOE) to indicate the strength of support for that association. Evidence from the pharmacogenomic literature is curated into PharmGKB as variant annotations, which can be used to create new clinical annotations or added to existing clinical annotations. This means that the same clinical annotation can be worked on by multiple curators over time. As more evidence is curated into PharmGKB, the task of maintaining consistency when assessing all the available evidence and assigning an LOE becomes increasingly difficult. To remedy this, a scoring system has been developed to automate LOE assignment to clinical annotations. Variant annotations are scored according to certain attributes, including study size, reported P value, and whether the variant annotation supports or fails to find an association. Clinical guidelines or US Food and Drug Administration (FDA)-approved drug labels which give variant-specific prescribing guidance are also scored. The scores of all annotations attached to a clinical annotation are summed together to give a total score for the clinical annotation, which is used to calculate an LOE. Overall, the system increases transparency, consistency, and reproducibility in LOE assignment to clinical annotations. In combination with increased standardization of how clinical annotations are written, use of this scoring system helps to ensure that PharmGKB clinical annotations continue to be a robust source of pharmacogenomic information.
Subject(s)
Pharmacogenetics/standards , Precision Medicine/standards , Databases, Genetic/standards , Drug Labeling/standards , Drug Prescriptions/standards , Humans , Knowledge Bases , Prescription Drugs/standards , Reproducibility of ResultsABSTRACT
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).
Subject(s)
Cytochrome P-450 CYP2C9/genetics , HLA-B Antigens/genetics , Phenytoin/administration & dosage , Alleles , Anticonvulsants/administration & dosage , Genetic Variation/genetics , Genotype , Humans , Pharmacogenetics/methods , Stevens-Johnson Syndrome/drug therapy , Stevens-Johnson Syndrome/geneticsABSTRACT
Opioids are mainly used to treat both acute and chronic pain. Several opioids are metabolized to some extent by CYP2D6 (codeine, tramadol, hydrocodone, oxycodone, and methadone). Polymorphisms in CYP2D6 have been studied for an association with the clinical effect and safety of these drugs. Other genes that have been studied for their association with opioid clinical effect or adverse events include OPRM1 (mu receptor) and COMT (catechol-O-methyltransferase). This guideline updates and expands the 2014 Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for CYP2D6 genotype and codeine therapy and includes a summation of the evidence describing the impact of CYP2D6, OPRM1, and COMT on opioid analgesia and adverse events. We provide therapeutic recommendations for the use of CYP2D6 genotype results for prescribing codeine and tramadol and describe the limited and/or weak data for CYP2D6 and hydrocodone, oxycodone, and methadone, and for OPRM1 and COMT for clinical use.
Subject(s)
Analgesics, Opioid/therapeutic use , Catechol O-Methyltransferase/genetics , Cytochrome P-450 CYP2D6/genetics , Pain/drug therapy , Receptors, Opioid, mu/genetics , Genotype , Humans , Pharmacogenomic Testing , Pharmacogenomic VariantsABSTRACT
Precision medicine tailors treatment to individuals personal data including differences in their genome. The Pharmacogenomics Knowledgebase (PharmGKB) provides highly curated information on the effect of genetic variation on drug response and side effects for a wide range of drugs. PharmGKB's scientific curators triage, review and annotate a large number of papers each year but the task is challenging. We present the PGxMine resource, a text-mined resource of pharmacogenomic associations from all accessible published literature to assist in the curation of PharmGKB. We developed a supervised machine learning pipeline to extract associations between a variant (DNA and protein changes, star alleles and dbSNP identifiers) and a chemical. PGxMine covers 452 chemicals and 2,426 variants and contains 19,930 mentions of pharmacogenomic associations across 7,170 papers. An evaluation by PharmGKB curators found that 57 of the top 100 associations not found in PharmGKB led to 83 curatable papers and a further 24 associations would likely lead to curatable papers through citations. The results can be viewed at https://pgxmine.pharmgkb.org/ and code can be downloaded at https://github.com/jakelever/pgxmine.
Subject(s)
Pharmacogenetics , Precision Medicine , Computational Biology , Data Mining/methods , Databases, Genetic , Humans , Knowledge Bases , Precision Medicine/methodsABSTRACT
Pharmacogenomics aims to associate human genetic variability with differences in drug phenotypes in order to tailor drug treatment to individual patients. The massive amount of genetic data generated from large cohorts of patients with variable drug phenotypes have led to advances in this field. Understanding the application of pharmacogenomics in dermatology could inform clinical practice and provide insight for future research. The Pharmacogenomics Knowledge Base and the Clinical Pharmacogenetics Implementation Consortium are among the resources to help clinicians and researchers navigate the many gene-drug associations that have already been discovered. The implementation of clinical pharmacogenomics within health care systems remains an area of ongoing development. This review provides an introduction to the field of pharmacogenomics and to current pharmacogenomics resources using examples of gene-drug associations relevant to the field of dermatology.
Subject(s)
Databases, Factual , Pharmacogenetics , Skin Diseases/drug therapy , Dermatologic Agents/adverse effects , Dermatologic Agents/therapeutic use , Drug-Related Side Effects and Adverse Reactions/prevention & control , Humans , Precision MedicineABSTRACT
The varying frequencies of pharmacogenetic alleles among populations have important implications for the impact of these alleles in different populations. Current population grouping methods to communicate these patterns are insufficient as they are inconsistent and fail to reflect the global distribution of genetic variability. To facilitate and standardize the reporting of variability in pharmacogenetic allele frequencies, we present seven geographically defined groups: American, Central/South Asian, East Asian, European, Near Eastern, Oceanian, and Sub-Saharan African, and two admixed groups: African American/Afro-Caribbean and Latino. These nine groups are defined by global autosomal genetic structure and based on data from large-scale sequencing initiatives. We recognize that broadly grouping global populations is an oversimplification of human diversity and does not capture complex social and cultural identity. However, these groups meet a key need in pharmacogenetics research by enabling consistent communication of the scale of variability in global allele frequencies and are now used by Pharmacogenomics Knowledgebase (PharmGKB).
Subject(s)
Genetics, Population/methods , Geographic Mapping , Pharmacogenetics/methods , Population Groups , Classification , Gene Frequency , Genetic Variation , Humans , Pharmacogenomic Testing , Population Groups/classification , Population Groups/genetics , Topography, MedicalSubject(s)
Drug Resistance/genetics , Drug-Related Side Effects and Adverse Reactions/genetics , Drug-Related Side Effects and Adverse Reactions/prevention & control , Humans , Pharmacogenetics/methods , Pharmacogenomic Variants/genetics , Precision Medicine/methods , Randomized Controlled Trials as TopicABSTRACT
Currently, no vaccine exists for hepatitis C virus (HCV), a major pathogen thought to infect 170 million people globally. Many studies suggest that host T cell responses are critical for spontaneous resolution of disease, and preclinical studies have indicated a requirement for T cells in protection against challenge. We aimed to elicit HCV-specific T cells with the potential for protection using a recombinant adenoviral vector strategy in a phase 1 study of healthy human volunteers. Two adenoviral vectors expressing NS proteins from HCV genotype 1B were constructed based on rare serotypes [human adenovirus 6 (Ad6) and chimpanzee adenovirus 3 (ChAd3)]. Both vectors primed T cell responses against HCV proteins; these T cell responses targeted multiple proteins and were capable of recognizing heterologous strains (genotypes 1A and 3A). HCV-specific T cells consisted of both CD4+ and CD8+ T cell subsets; secreted interleukin-2, interferon-γ, and tumor necrosis factor-α; and could be sustained for at least a year after boosting with the heterologous adenoviral vector. Studies using major histocompatibility complex peptide tetramers revealed long-lived central and effector memory pools that retained polyfunctionality and proliferative capacity. These data indicate that an adenoviral vector strategy can induce sustained T cell responses of a magnitude and quality associated with protective immunity and open the way for studies of prophylactic and therapeutic vaccines for HCV.