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Methods in Molecular Biology (Clifton,... 2022Historically genetics has not been considered when prescribing drugs for children. However, it is clear that genetics are not only an important determinant of disease in...
Historically genetics has not been considered when prescribing drugs for children. However, it is clear that genetics are not only an important determinant of disease in children but also of drug response for many important drugs that are core agents used in the therapy of common problems in children. Advances in therapy and in the ethical construct of children's research have made pharmacogenomic assessment for children much easier to pursue. It is likely that pharmacogenomics will become part of the therapeutic decision-making process for children, notably in areas such as childhood cancer where weighing benefits and risks of therapy is crucial.
Topics: Child; Humans; Neoplasms; Pharmacogenetics
PubMed: 36068477
DOI: 10.1007/978-1-0716-2573-6_20 -
Current Protocols Jul 2021Cardiovascular pharmacogenomics is the study and identification of genomic markers that are associated with variability in cardiovascular drug response, cardiovascular...
Cardiovascular pharmacogenomics is the study and identification of genomic markers that are associated with variability in cardiovascular drug response, cardiovascular drug-related outcomes, or cardiovascular drug-related adverse events. This overview presents an introduction and historical background to cardiovascular pharmacogenomics, and a protocol for designing a cardiovascular pharmacogenomics study. Important considerations are also included for constructing a cardiovascular pharmacogenomics phenotype, designing the replication or validation strategy, common statistical approaches, and how to put the results in context with the cardiovascular drug or cardiovascular disease under investigation. © 2021 Wiley Periodicals LLC. Basic Protocol: Designing a cardiovascular pharmacogenomics study.
Topics: Cardiovascular Agents; Cardiovascular Diseases; Humans; Pharmacogenetics; Pharmacogenomic Testing; Phenotype
PubMed: 34232575
DOI: 10.1002/cpz1.189 -
Clinical Pharmacology and Therapeutics Sep 2021The increasing availability of genotype data linked with information about drug-response phenotypes has enabled genomewide association studies (GWAS) that uncover... (Review)
Review
The increasing availability of genotype data linked with information about drug-response phenotypes has enabled genomewide association studies (GWAS) that uncover genetic determinants of drug response. GWAS have discovered associations between genetic variants and both drug efficacy and adverse drug reactions. Despite these successes, the design of GWAS in pharmacogenomics (PGx) faces unique challenges. In this review, we analyze the last decade of GWAS in PGx. We review trends in publications over time, including the drugs and drug classes studied and the clinical phenotypes used. Several data sharing consortia have contributed substantially to the PGx GWAS literature. We anticipate increased focus on biobanks and highlight phenotypes that would best enable future PGx discoveries.
Topics: Drug-Related Side Effects and Adverse Reactions; Genome-Wide Association Study; Genotype; Humans; Pharmacogenetics; Phenotype
PubMed: 34185318
DOI: 10.1002/cpt.2349 -
Clinical Laboratory Aug 2023Next-generation sequencing (NGS) methods have become more commonly performed in clinical and research laboratories. (Review)
Review
BACKGROUND
Next-generation sequencing (NGS) methods have become more commonly performed in clinical and research laboratories.
METHODS
This review summarizes the current laboratory NGS-based diagnostic approaches in pharmacogenomics including targeted multi-gene panel sequencing, whole-exome sequencing (WES), and whole-genome sequencing (WGS).
RESULTS
Clinical laboratories perform multiple non-uniform types of pharmacogenetic panels, which can reduce the overall number of single-gene tests to be more cost-efficient. Compared to the targeted multi-gene panels, which are not typically designed to detect novel variants, WES and WGS have a greater potential to identify secondary pharmacogenomic findings, which might be predictive for the pharmacotherapy outcome of different patient settings. WGS overcomes the limitations of WES enabling a more accurate exome-sequencing at appropriate coverage and the sequencing of non-coding regions. Different NGS-based study designs with different test strategies and study populations, varying sample sizes, and distinct analytical and interpretation procedures lead to different identification results of pharmacogenomic variants.
CONCLUSIONS
The rapid progress in gene sequencing technologies will overcome the clinical and laboratory challenges of WES and WGS. Further high throughput NGS-based pharmacogenomics studies in different populations and patient settings are necessary to expand knowledge about rare functional variants and to enhance translation in clinical practice.
Topics: Humans; Pharmacogenetics; High-Throughput Nucleotide Sequencing
PubMed: 37560847
DOI: 10.7754/Clin.Lab.2023.230103 -
Supportive Care in Cancer : Official... Dec 2022Studies suggest wide heterogeneity in pain management response. Improved methods of pain pharmacotherapy are urgently needed to improve clinical response and safety... (Review)
Review
Studies suggest wide heterogeneity in pain management response. Improved methods of pain pharmacotherapy are urgently needed to improve clinical response and safety profile of analgesics. The study or application of how genetics influence response to medications is called pharmacogenomics (PGx). PGx testing is a tool that may support more precise selection and dosing of pain medicines. PGx guidelines exist for drug-gene interactions with high levels of evidence and can be applied in clinical practice for more precise care in patients with cancer. The Clinical Pharmacogenetics Implementation Consortium (CPIC) is a publicly funded international consortium of experts who curate published PGx data and create peer-reviewed guidelines on how to translate PGx results into actionable prescribing decisions. Given the immense need to improve pain management, it is important to increase awareness and consider application of CPIC guidelines to pain management strategies. This commentary concisely describes how PGx can be used to aid in more precise applications of pain pharmacotherapy based on the CPIC guidelines.
Topics: Humans; Pharmacogenetics; Pain Management; Pain
PubMed: 36271058
DOI: 10.1007/s00520-022-07404-9 -
Current Opinion in Pediatrics Dec 2021Pharmacogenomic insights provide an opportunity to optimize medication dosing regimens and patient outcomes. However, the potential for interindividual genomic... (Review)
Review
PURPOSE OF REVIEW
Pharmacogenomic insights provide an opportunity to optimize medication dosing regimens and patient outcomes. However, the potential for interindividual genomic variability to guide medication dosing and toxicity monitoring is not yet standard of care. In this review, we present advances for the thiopurines, anthracyclines and vincristine and provide perspectives on the actionability of pharmacogenomic guidance in the future.
RECENT FINDINGS
The current guideline on thiopurines recommends that those with normal predicted thiopurine methyltransferase and NUDT15 expression receive standard-of-care dosing, while 'poor metabolizer' haplotypes receive a decreased 6-mercaptopurine starting dose to avoid bone marrow toxicity. Emerging evidence established significant polygenic contributions that predispose to anthracycline-induced cardiotoxicity and suggest this knowledge be used to identify those at higher risk of complications. In the case of vincristine, children who express CYP3A5 have a significantly reduced risk of peripheral neuropathy compared with those expressing an inactive form or the CYP3A4 isoform.
SUMMARY
The need for adequately powered pediatric clinical trials, coupled with the study of epigenetic mechanisms and their influence on phenotypic variation and the integration of precision survivorship into precision approaches are featured as important areas for focused investments in the future.
Topics: Cardiotoxicity; Child; Humans; Medical Oncology; Mercaptopurine; Neoplasms; Pharmacogenetics
PubMed: 34561358
DOI: 10.1097/MOP.0000000000001065 -
Clinical Therapeutics May 2021
Topics: Artificial Intelligence; Humans; Pharmacogenetics; Precision Medicine
PubMed: 34052008
DOI: 10.1016/j.clinthera.2021.04.005 -
Annual Review of Pharmacology and... Jan 2020Pharmacogenetics is a key component of precision medicine. Genetic variation in drug metabolism enzymes can lead to variable exposure to drugs and metabolites,... (Review)
Review
Pharmacogenetics is a key component of precision medicine. Genetic variation in drug metabolism enzymes can lead to variable exposure to drugs and metabolites, potentially leading to inefficacy and drug toxicity. Although the evidence for pharmacogenetic associations in children is not as extensive as for adults, there are several drugs across diverse therapeutic areas with robust pediatric data indicating important, and relatively common, drug-gene interactions. Guidelines to assist gene-based dose optimization are available for codeine, thiopurine drugs, selective serotonin reuptake inhibitors, atomoxetine, tacrolimus, and voriconazole. For each of these drugs, there is an opportunity to clinically implement precision medicine approaches with children for whom genetic test results are known or are obtained at the time of prescribing. For many more drugs that are commonly used in pediatric patients, additional investigation is needed to determine the genetic factors influencing appropriate dose.
Topics: Child; Dose-Response Relationship, Drug; Drug-Related Side Effects and Adverse Reactions; Humans; Pharmaceutical Preparations; Pharmacogenetics; Precision Medicine
PubMed: 31283429
DOI: 10.1146/annurev-pharmtox-010919-023459 -
Neuroscience Letters May 2020Neurodegenerative disorders (NDDs)(Alzheimer's disease, Parkinson's disease) represent major problems of health in developed countries, with important psychosocial... (Review)
Review
Neurodegenerative disorders (NDDs)(Alzheimer's disease, Parkinson's disease) represent major problems of health in developed countries, with important psychosocial burden for families and high cost for the society. NDDs share some common pathogenic mechanisms such as age-related decline, multiple genetic defects distributed across the genome, deposits of abnormal proteins in the brain, and diverse environmental risk factors. Patients with NDDs currently receive polypharmacy with a high risk for drug-drug interactions and severe adverse drug events. Pharmacogenomics accounts for 60-90% variability in drug pharmacokinetics and pharmacodynamics. Major determinants of the pharmacogenomic outcome include pathogenic, mechanistic, metabolic, transporter and pleiotropic genes. The expression of these genes is under regulatory control of the epigenetic machinery. Approximately, 80% of the Caucasian population is deficient in the metabolization of drugs due to polymorphisms in metabolic genes; consequently, less than 40% of patients respond appropriately to conventional drugs. The implementation of pharmacogenomic procedures in the clinical practice may help to optimize therapeutics in NDDs.
Topics: Alzheimer Disease; Animals; Antiparkinson Agents; Dopamine Agents; Humans; Parkinson Disease; Pharmacogenetics; Polymorphism, Genetic
PubMed: 30236877
DOI: 10.1016/j.neulet.2018.09.018 -
Genes Sep 2023Health equity means the opportunity for all people and populations to attain optimal health, and it requires intentional efforts to promote fairness in patient...
Health equity means the opportunity for all people and populations to attain optimal health, and it requires intentional efforts to promote fairness in patient treatments and outcomes. Pharmacogenomic variants are genetic differences associated with how patients respond to medications, and their presence can inform treatment decisions. In this perspective, we contend that the study of pharmacogenomic variation within and between human populations-population pharmacogenomics-can and should be leveraged in support of health equity. The key observation in support of this contention is that racial and ethnic groups exhibit pronounced differences in the frequencies of numerous pharmacogenomic variants, with direct implications for clinical practice. The use of race and ethnicity to stratify pharmacogenomic risk provides a means to avoid potential harm caused by biases introduced when treatment regimens do not consider genetic differences between population groups, particularly when majority group genetic profiles are assumed to hold for minority groups. We focus on the mitigation of adverse drug reactions as an area where population pharmacogenomics can have a direct and immediate impact on public health.
Topics: Humans; Pharmacogenetics; Health Equity; Ethnicity; Pharmacogenomic Variants; Minority Groups
PubMed: 37895188
DOI: 10.3390/genes14101840