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Human Molecular Genetics Apr 2006The field of pharmacogenomics has seen some exciting advances in the recent past. The Human Genome Project and International HapMap projects have uncovered a wealth of... (Review)
Review
The field of pharmacogenomics has seen some exciting advances in the recent past. The Human Genome Project and International HapMap projects have uncovered a wealth of information for researchers. The discovery of clinically predictive genotypes (e.g. UGT1A1*28, TYMS TSER), haplotypes (e.g. VKORC1 Haplotype A) and somatic mutations (e.g. epidermal growth factor receptor), along with the introduction of FDA approved pharmacogenetic tests (UGT1A1*28) and the initiation of a genotype-guided clinical trial for cancer therapy (TYMS TSER in rectal cancer) have provided the first steps towards the integration of pharmacogenomics into clinical practice. This review describes some of the recent advances in pharmacogenomics research.
Topics: Genotype; Humans; Mutation; Neoplasms; Pharmacogenetics; Polymorphism, Genetic
PubMed: 16651374
DOI: 10.1093/hmg/ddl087 -
Nature Biotechnology Nov 2012Genome-wide association studies (GWAS) of responses to drugs, including clopidogrel, pegylated-interferon and carbamazepine, have led to the identification of specific... (Review)
Review
Genome-wide association studies (GWAS) of responses to drugs, including clopidogrel, pegylated-interferon and carbamazepine, have led to the identification of specific patient subgroups that benefit from therapy. However, the identification and replication of common sequence variants that are associated with either efficacy or safety for most prescription medications at odds ratios (ORs) >3.0 (equivalent to >300% increased efficacy or safety) has yet to be translated to clinical practice. Although some of the studies have been completed, the results have not been incorporated into therapy, and a large number of commonly used medications have not been subject to proper pharmacogenomic analysis. Adoption of GWAS, exome or whole genome sequencing by drug development and treatment programs is the most striking near-term opportunity for improving the drug candidate pipeline and boosting the efficacy of medications already in use.
Topics: Animals; Chromosome Mapping; Drug Design; Genetic Predisposition to Disease; Humans; Pharmacogenetics; Sequence Analysis, DNA
PubMed: 23138311
DOI: 10.1038/nbt.2424 -
Basic & Clinical Pharmacology &... Dec 2022Genetic factors have long been recognized as important determinants of interindividual variability in drug efficacy and toxicity. However, despite the increasing number... (Review)
Review
Genetic factors have long been recognized as important determinants of interindividual variability in drug efficacy and toxicity. However, despite the increasing number of established gene-drug associations, candidate polymorphisms can only explain a fraction of the genetically encoded functional variability in drug disposition. Advancements in genetic profiling methods now allow to analyse the landscape of human pharmacogenetic variations comprehensively, which opens new opportunities to identify novel factors that could explain the "missing heritability." Here, we provide an updated overview of the landscape of pharmacogenomic variability based on recent analyses of population-scale sequencing projects. We then summarize the current state-of-the-art how the functional consequences of variants with unknown effects can be quantitatively estimated while discussing challenges and peculiarities that are specific to pharmacogenes. In the last sections, we discuss the importance of considering ethnogeographic diversity to provide equitable benefits of pharmacogenomics and summarize current roadblocks for the implementation of sequencing-based guidance of clinical decision-making. Based on the current state of the field, we conclude that testing is likely to gradually shift from the interrogation of selected candidate polymorphisms to comprehensive sequencing, which allows to consider the full spectrum of pharmacogenomic variations for a true personalization of genomic prescribing.
Topics: Humans; Pharmacogenetics; High-Throughput Nucleotide Sequencing; Polymorphism, Genetic; Sequence Analysis, DNA
PubMed: 35971800
DOI: 10.1111/bcpt.13779 -
American Journal of Health-system... Dec 2016Existing pharmacogenomic informatics models, key implementation steps, and emerging resources to facilitate the development of pharmacogenomic clinical decision support... (Review)
Review
PURPOSE
Existing pharmacogenomic informatics models, key implementation steps, and emerging resources to facilitate the development of pharmacogenomic clinical decision support (CDS) are described.
SUMMARY
Pharmacogenomics is an important component of precision medicine. Informatics, especially CDS in the electronic health record (EHR), is a critical tool for the integration of pharmacogenomics into routine patient care. Effective integration of pharmacogenomic CDS into the EHR can address implementation challenges, including the increasing volume of pharmacogenomic clinical knowledge, the enduring nature of pharmacogenomic test results, and the complexity of interpreting results. Both passive and active CDS provide point-of-care information to clinicians that can guide the systematic use of pharmacogenomics to proactively optimize pharmacotherapy. Key considerations for a successful implementation have been identified; these include clinical workflows, identification of alert triggers, and tools to guide interpretation of results. These considerations, along with emerging resources from the Clinical Pharmacogenetics Implementation Consortium and the National Academy of Medicine, are described.
CONCLUSION
The EHR with CDS is essential to curate pharmacogenomic data and disseminate patient-specific information at the point of care. As part of the successful implementation of pharmacogenomics into clinical settings, all relevant clinical recommendations pertaining to gene-drug pairs must be summarized and presented to clinicians in a manner that is seamlessly integrated into the clinical workflow of the EHR. In some situations, ancillary systems and applications outside the EHR may be integrated to augment the capabilities of the EHR.
Topics: Decision Support Systems, Clinical; Electronic Health Records; Humans; Pharmacogenetics; Point-of-Care Systems; Precision Medicine
PubMed: 27864204
DOI: 10.2146/ajhp160030 -
The Pharmacogenomics Journal 2003UDP-glucuronosyltransferase (UGT) enzymes comprise a superfamily of key proteins that catalyze the glucuronidation reaction on a wide range of structurally diverse... (Review)
Review
UDP-glucuronosyltransferase (UGT) enzymes comprise a superfamily of key proteins that catalyze the glucuronidation reaction on a wide range of structurally diverse endogenous and exogenous chemicals. Glucuronidation is one of the major phase II drug-metabolizing reactions that contributes to drug biotransformation. This biochemical process is also involved in the protection against environmental toxicants, carcinogens, dietary toxins and participates in the homeostasis of numerous endogenous molecules, including bilirubin, steroid hormones and biliary acids. Over the years, significant progress was made in the field of glucuronidation, especially with regard to the identification of human UGTs, study of their tissue distribution and substrate specificities. More recently, the degree of allelic diversity has also been revealed for several human UGT genes. Some polymorphic UGTs have demonstrated a significant pharmacological impact in addition to being relevant to drug-induced adverse reactions and cancer susceptibility. This review focuses on human UGTs, the description of the nature of polymorphic variations and their functional impact. The pharmacogenomic implication of polymorphic UGTs is presented, more specifically the role of UGT polymorphisms in modifying cancer risk and their impact on individual risk to drug-induced toxicities.
Topics: Animals; Glucuronosyltransferase; Humans; Pharmacogenetics
PubMed: 12815363
DOI: 10.1038/sj.tpj.6500171 -
Cellular and Molecular Neurobiology 20061. Pharmacogenomics is the study of the role of inheritance in variation in the drug response phenotype-a phenotype that can vary from adverse drug reactions at one end... (Review)
Review
1. Pharmacogenomics is the study of the role of inheritance in variation in the drug response phenotype-a phenotype that can vary from adverse drug reactions at one end of the spectrum to lack of therapeutic efficacy at the other. 2. The thiopurine S-methyltransferase (TPMT) genetic polymorphism represents one of the best characterized and most clinically relevant examples of pharmacogenomics. This polymorphism has also served as a valuable "model system" for studies of the ways in which variation in DNA sequence might influence function. 3. The discovery and characterization of the TPMT polymorphism grew directly out of pharmacogenomic studies of catechol O-methyltransferase (COMT), an enzyme discovered by Julius (Julie) Axelrod and his coworkers. 4. This review will outline the process by which common, functionally significant genetic polymorphisms for both COMT and TPMT were discovered and will use these two methyltransferase enzymes to illustrate general principles of pharmacogenomic research-both basic mechanistic and clinical translational research-principles that have been applied to a series of genes encoding methyltransferase enzymes.
Topics: Animals; Catechol O-Methyltransferase; Humans; Inactivation, Metabolic; Methylation; Methyltransferases; Models, Biological; Pharmacogenetics; Polymorphism, Genetic
PubMed: 16807786
DOI: 10.1007/s10571-006-9095-z -
Clinical Pharmacology and Therapeutics Jul 2009The development of robust and clinically valuable pharmacogenomic tests has been anticipated to be one of the first tangible results of the Human Genome Project. Despite... (Review)
Review
The development of robust and clinically valuable pharmacogenomic tests has been anticipated to be one of the first tangible results of the Human Genome Project. Despite both obvious and unanticipated obstacles, a number of tests have now become available in various practice settings. Lessons can be learned from examination of these tests, the evidence that has catalyzed their use, their value to prescribers, and their merit as tools for personalizing therapeutics.
Topics: Animals; Drug Industry; Genome, Human; Genotype; Humans; Pharmacogenetics
PubMed: 19369936
DOI: 10.1038/clpt.2009.39 -
American Journal of Health-system... Dec 2016
Topics: Humans; Pharmacists; Pharmacogenetics; Precision Medicine; Professional Role
PubMed: 27784662
DOI: 10.2146/ajhp160682 -
Human Genetics May 2015Understanding the role genes and genetic variants play in clinical treatment response continues to be an active area of research with the goal of common clinical use.... (Review)
Review
Understanding the role genes and genetic variants play in clinical treatment response continues to be an active area of research with the goal of common clinical use. This goal has developed into today's industry of pharmacogenomics, where new drug-gene relationships are discovered and further characterized, published and then curated into national and international resources for use by researchers and clinicians. These efforts have given us insight into what a pharmacogenomic variant is, and how it differs from human disease variants and common polymorphisms. While publications continue to reveal pharmacogenomic relationships between genes and specific classes of drugs, many challenges remain toward the goal of widespread use clinically. First, the clinical guidelines for pharmacogenomic testing are still in their infancy. Second, sequencing technologies are changing rapidly making it somewhat unclear what genetic data will be available to the clinician at the time of care. Finally, what and when to return data to a patient is an area under constant debate. New innovations such as PheWAS approaches and whole genome sequencing studies are enabling a tsunami of new findings. In this review, pharmacogenomic variants, pharmacogenomic resources, interpretation clinical guidelines and challenges, such as WGS approaches, and the impact of pharmacogenomics on drug development and regulatory approval are reviewed.
Topics: Computational Biology; Data Interpretation, Statistical; Databases, Genetic; Databases, Pharmaceutical; Drug Discovery; Genetic Variation; Humans; Pharmacogenetics; Phenotype
PubMed: 25238897
DOI: 10.1007/s00439-014-1484-7 -
Pharmacogenomics Jun 2019The appropriate use and integration of pharmacogenetic (PGx) testing will pivot on provider preparation and training. Pharmacists have been recognized as one of the key...
The appropriate use and integration of pharmacogenetic (PGx) testing will pivot on provider preparation and training. Pharmacists have been recognized as one of the key providers in the delivery of PGx testing and as such, professional organizations have recommended inclusion of PGx content in pharmacy curricula. We reviewed the curriculum of 132 US pharmacy schools for information about PGx courses. A total of 70 core curriculum courses were identified. 55 (42%) pharmacy schools included at least one PGx course as part of the core curriculum, and ten (8%) schools that offered a PGx course elective. While many pharmacy schools have responded to the accreditation standards to include PGx, less than half of the schools have developed a standalone course.
Topics: Curriculum; Education, Pharmacy; Pharmacogenetics; Pharmacogenomic Testing; Precision Medicine; Schools, Pharmacy; Students, Pharmacy; United States
PubMed: 31250728
DOI: 10.2217/pgs-2019-0024