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PloS One 2022The accurate identification of genetic variants contributing to therapeutic drug response or adverse effects is the first step in implementation of precision drug...
The accurate identification of genetic variants contributing to therapeutic drug response or adverse effects is the first step in implementation of precision drug therapy. Targeted sequencing has recently become a common methodology for large-scale studies of genetic variation thanks to its favorable balance between low cost, high throughput, and deep coverage. Here, we present ClinPharmSeq, a targeted sequencing panel of 59 genes with associations to pharmacogenetic (PGx) phenotypes, as a platform to explore the relationship between drug response and genetic variation, both common and rare. For validation, we sequenced DNA from 64 ethnically diverse Coriell samples with ClinPharmSeq to call star alleles (haplotype patterns) in 27 genes using the bioinformatics tool PyPGx. These reference samples were extensively characterized by multiple laboratories using PGx testing assays and, more recently, whole genome sequencing. We found that ClinPharmSeq can consistently generate deep-coverage data (mean = 274x) with high uniformity (30x or above = 94.8%). Our genotype analysis identified a total of 185 unique star alleles from sequencing data, and showed that diplotype calls from ClinPharmSeq are highly concordant with that from previous publications (97.6%) and whole genome sequencing (97.9%). Notably, all 19 star alleles with complex structural variation including gene deletions, duplications, and hybrids were recalled with 100% accuracy. Altogether, these results demonstrate that the ClinPharmSeq platform offers a feasible path for broad implementation of PGx testing and optimization of individual drug treatments.
Topics: Alleles; Genotype; Haplotypes; High-Throughput Nucleotide Sequencing; Pharmacogenetics; Whole Genome Sequencing
PubMed: 35901010
DOI: 10.1371/journal.pone.0272129 -
American Journal of Health-system... Jul 2009
Topics: Cooperative Behavior; Humans; Pharmacists; Pharmacogenetics
PubMed: 19574597
DOI: 10.2146/ajhp090152 -
Neuropsychopharmacology : Official... Nov 2013The integration of research on neuroimaging and pharmacogenetics holds promise for improving treatment for neuropsychiatric conditions. Neuroimaging may provide a more... (Review)
Review
The integration of research on neuroimaging and pharmacogenetics holds promise for improving treatment for neuropsychiatric conditions. Neuroimaging may provide a more sensitive early measure of treatment response in genetically defined patient groups, and could facilitate development of novel therapies based on an improved understanding of pathogenic mechanisms underlying pharmacogenetic associations. This review summarizes progress in efforts to incorporate neuroimaging into genetics and treatment research on major psychiatric disorders, such as schizophrenia, major depressive disorder, bipolar disorder, attention-deficit/hyperactivity disorder, and addiction. Methodological challenges include: performing genetic analyses in small study populations used in imaging studies; inclusion of patients with psychiatric comorbidities; and the extensive variability across studies in neuroimaging protocols, neurobehavioral task probes, and analytic strategies. Moreover, few studies use pharmacogenetic designs that permit testing of genotype × drug effects. As a result of these limitations, few findings have been fully replicated. Future studies that pre-screen participants for genetic variants selected a priori based on drug metabolism and targets have the greatest potential to advance the science and practice of psychiatric treatment.
Topics: Humans; Mental Disorders; Mental Processes; Neuroimaging; Pharmacogenetics
PubMed: 23793356
DOI: 10.1038/npp.2013.152 -
Molecular Diagnosis & Therapy Apr 2010Systemic and biologic treatments used for the treatment of moderate to severe psoriasis show significant variability in efficacy, are associated with varying degrees of... (Review)
Review
Systemic and biologic treatments used for the treatment of moderate to severe psoriasis show significant variability in efficacy, are associated with varying degrees of toxicity and, in the case of biologic therapies, are expensive. There is a great need for non-invasive biomarkers to predict treatment outcomes from these therapies and individualize care for psoriasis patients. Identification of pharmacogenetic and pharmacogenomic markers of treatment response may be useful in predicting clinical response to psoriasis therapies and would help in the development of individually tailored treatment. This would increase the cost effectiveness of treatment and reduce unnecessary exposure to treatment toxicity. This review details the current status of pharmacogenetic and pharmacogenomic markers in psoriasis and explores how these research tools may ultimately lead to safer, more directed treatments. Until now, pharmacogenetic studies in psoriasis have been underpowered to produce reliable results, and many have not recorded treatment response or toxicities prospectively in an objective and reproducible manner. Large-scale collaborations and use of patient registries for systemic and biologic treatments in well characterized patient populations that are uniformly treated and systemically evaluated could play a valuable role in advancing the field of pharmacogenetics and pharmacogenomics of psoriasis.
Topics: Administration, Topical; Animals; Dermatologic Agents; Genetic Markers; Humans; Pharmacogenetics; Psoriasis
PubMed: 20359251
DOI: 10.1007/BF03256357 -
Drug Safety 2001In the US, adverse drug reactions (ADRs) rank between the fourth to sixth leading cause of death, ahead of pneumonia and diabetes mellitus. An important reason for the... (Review)
Review
In the US, adverse drug reactions (ADRs) rank between the fourth to sixth leading cause of death, ahead of pneumonia and diabetes mellitus. An important reason for the high incidence of serious and fatal ADRs is that the existing drug development paradigms do not generate adequate information on the mechanistic sources of marked variability in pharmacokinetics and pharmacodynamics of new therapeutic candidates, precluding treatments from being tailored for individual patients. Pharmacogenetics is the study of the hereditary basis of person-to-person variations in drug response. The focus of pharmacogenetic investigations has traditionally been unusual and extreme drug responses resulting from a single gene effect. The Human Genome Project and recent advancements in molecular genetics now present an unprecedented opportunity to study all genes in the human genome, including genes for drug metabolism, drug targets and postreceptor second messenger machinery, in relation to variability in drug safety and efficacy. In addition to sequence variations in the genome, high throughput and genome-wide transcript profiling for differentially regulated mRNA species before and during drug treatment will serve as important tools to uncover novel mechanisms of drug action. Pharmacogenetic-guided drug discovery and development represent a departure from the conventional approach which markets drugs for broad patient populations, rather than smaller groups of patients in whom drugs may work more optimally. Pharmacogenetics provides a rational framework to minimise the uncertainty in outcome of drug therapy and clinical trials and thereby should significantly reduce the risk of drug toxicity.
Topics: Drug Evaluation; Drug-Related Side Effects and Adverse Reactions; Human Genome Project; Humans; Internet; Molecular Biology; Pharmaceutical Preparations; Pharmacogenetics; Pharmacokinetics; Pharmacology
PubMed: 11235820
DOI: 10.2165/00002018-200124020-00001 -
Psychopharmacology Jun 2002Pharmacogenetic research has identified response-related mutant variants in metabolic enzymes and drug-targeted receptors. Allelic variants of dopaminergic and... (Review)
Review
Pharmacogenetic research has identified response-related mutant variants in metabolic enzymes and drug-targeted receptors. Allelic variants of dopaminergic and serotonergic receptors have been associated with clinical outcome and adverse events such as movement disorders. Deficient metabolic enzymes have been related to drug accumulation and toxic events. This information will help to design safer and more efficient drugs. However, the field is moving rapidly towards a new goal: the application of pharmacogenetics as a clinical tool for the prediction of treatment outcome. The first studies in this direction have proved the feasibility of using genetic information for the prediction of response to antipsychotic drugs and to treatment of Alzheimer's disease. New strategies investigating genes related to specific symptoms and side-effects have produced encouraging results that can contribute to the improvement of the levels and accuracy of the predictions. This review tries to summarise recent advances and provides an overview of future clinical applications.
Topics: Humans; Mental Disorders; Pharmacogenetics; Polymorphism, Genetic; Psychiatry
PubMed: 12107612
DOI: 10.1007/s00213-002-1084-4 -
Pharmacogenomics 2015Currently available pharmacological treatments for alcoholism have modest efficacy and high individual variability in treatment outcomes, both of which have been... (Review)
Review
Currently available pharmacological treatments for alcoholism have modest efficacy and high individual variability in treatment outcomes, both of which have been partially attributed to genetic factors. One path to reducing the variability and improving the efficacy associated with these pharmacotherapies may be to identify overlapping genetic contributions to individual differences in both subjective responses to alcohol and alcoholism pharmacotherapy outcomes. As acute subjective response to alcohol is highly predictive of future alcohol related problems, identifying such shared genetic mechanisms may inform the development of personalized treatments that can effectively target converging pathophysiological mechanisms that convey risk for alcoholism. The focus of this review is to revisit the association between subjective response to alcohol and the etiology of alcoholism while also describing genetic contributions to this relationship, discuss potential pharmacogenetic approaches to target subjective response to alcohol in order to improve the treatment of alcoholism and examine conceptual and methodological issues associated with these topics, and outline future approaches to overcome these challenges.
Topics: Alcoholism; Animals; Attitude to Health; Humans; Narcotic Antagonists; Pharmacogenetics; Polymorphism, Single Nucleotide; Treatment Outcome
PubMed: 25950242
DOI: 10.2217/pgs.14.143 -
The Medical Clinics of North America Nov 2019Pharmacogenomics (PGx) is a powerful tool that can predict increased risks of adverse effects and sub-therapeutic response to medications. This article establishes the... (Review)
Review
Pharmacogenomics (PGx) is a powerful tool that can predict increased risks of adverse effects and sub-therapeutic response to medications. This article establishes the core principles necessary for a primary care provider to meaningfully and prudently use PGx testing. Key topics include in which patients PGx testing should be considered, how PGx tests are ordered, how the results are translated into clinical recommendations, and what further advancements are likely in the near future. This will provide clinicians with a foundational knowledge of PGx that can allow incorporation of this tool into their practice or support further personal investigation.
Topics: Drug-Related Side Effects and Adverse Reactions; Humans; Pharmacogenetics; Precision Medicine; Primary Health Care
PubMed: 31582008
DOI: 10.1016/j.mcna.2019.07.002 -
Clinical Pharmacology and Therapeutics May 2008Despite initial enthusiasm, the use of pharmacogenetics has remained limited to investigation in only a few clinical fields such as oncology and psychiatry. The main...
Despite initial enthusiasm, the use of pharmacogenetics has remained limited to investigation in only a few clinical fields such as oncology and psychiatry. The main reason is the paucity of scientific evidence to show that pharmacogenetic testing leads to improved clinical outcomes. Moreover, for most pharmacogenetic tests (such as tests for genetic variants of cytochrome P450 enzymes) a detailed knowledge of pharmacology is a prerequisite for application in clinical practice, and both physicians and pharmacists might find it difficult to interpret the clinical value of pharmacogenetic test results. Guidelines that link the result of a pharmacogenetic test to therapeutic recommendations might help to overcome these problems, but such guidelines are only sparsely available. In 2001, an early step was taken to develop such guidelines for the therapeutic use of antidepressants, and these included CYP2D6-related dose recommendations drawn from pharmacokinetic study data. However, the use of such recommendations in routine clinical practice remains difficult, because they are currently outside the ambit of the clinical environment and are not accessible during the decision-making process by physicians and pharmacists, namely the prescription and dispensing of drugs.
Topics: Drug Prescriptions; Drug Therapy, Computer-Assisted; Humans; Medication Systems; Pharmacogenetics; Pharmacokinetics; Practice Guidelines as Topic
PubMed: 18253145
DOI: 10.1038/sj.clpt.6100507 -
Pharmacogenomics Apr 2018Currently, there is sufficient evidence for the use of pharmacogenetic information to optimize medication prescribing, but why has this information not been integrated...
Currently, there is sufficient evidence for the use of pharmacogenetic information to optimize medication prescribing, but why has this information not been integrated into the drug prescribing process to improve patient care? A discussion about the major contributing factors that have limited the use of pharmacogenetic information in the drug prescribing process, the solutions to ensure widespread uptake, and a vision for the future of the pharmacogenetic field will be explored.
Topics: Delivery of Health Care; Drug Prescriptions; Genomics; Genotype; Humans; Pharmacogenetics; Pharmacogenomic Testing; Precision Medicine
PubMed: 29620450
DOI: 10.2217/pgs-2017-0192