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Annual Review of Pharmacology and... Jan 2019Race and ancestry have long been associated with differential risk and outcomes to disease as well as responses to medications. These differences in drug response are... (Review)
Review
Race and ancestry have long been associated with differential risk and outcomes to disease as well as responses to medications. These differences in drug response are multifactorial with some portion associated with genomic variation. The field of pharmacogenomics aims to predict drug response in patients prior to medication administration and to uncover the biological underpinnings of drug response. The field of human genetics has long recognized that genetic variation differs in frequency between ancestral populations, with some single nucleotide polymorphisms found solely in one population. Thus far, most pharmacogenomic studies have focused on individuals of European and East Asian ancestry, resulting in a substantial disparity in the clinical utility of genetic prediction for drug response in US minority populations. In this review, we discuss the genetic factors that underlie variability to drug response and known pharmacogenomic associations and how these differ between populations, with an emphasis on the current knowledge in cardiovascular pharmacogenomics.
Topics: Cardiovascular Diseases; Humans; Pharmacogenetics; Polymorphism, Single Nucleotide; Population Groups; Race Factors
PubMed: 30296897
DOI: 10.1146/annurev-pharmtox-010818-021154 -
Drug Metabolism Reviews May 2021Pharmacogenetic research has resulted in the identification of a multitude of genetic variants that impact drug response or toxicity. These polymorphisms are mostly... (Review)
Review
Pharmacogenetic research has resulted in the identification of a multitude of genetic variants that impact drug response or toxicity. These polymorphisms are mostly common and have been included as actionable information in the labels of numerous drugs. In addition to common variants, recent advances in Next Generation Sequencing (NGS) technologies have resulted in the identification of a plethora of rare and population-specific pharmacogenetic variations with unclear functional consequences that are not accessible by conventional forward genetics strategies. In this review, we discuss how comprehensive sequencing information can be translated into personalized pharmacogenomic advice in the age of NGS. Specifically, we provide an update of the functional impacts of rare pharmacogenetic variability and how this information can be leveraged to improve pharmacogenetic guidance. Furthermore, we critically discuss the current status of implementation of pharmacogenetic testing across drug development and layers of care. We identify major gaps and provide perspectives on how these can be minimized to optimize the utilization of NGS data for personalized clinical decision-support.
Topics: Drug Development; High-Throughput Nucleotide Sequencing; Humans; Pharmacogenetics; Polymorphism, Genetic
PubMed: 33820459
DOI: 10.1080/03602532.2021.1909613 -
Advances in Anatomic Pathology Jul 2004The discovery of the human genome and subsequent expansion of proteomics research combined with emerging technologies such as functional imaging, biosensors and... (Review)
Review
The discovery of the human genome and subsequent expansion of proteomics research combined with emerging technologies such as functional imaging, biosensors and sophisticated computational biology are producing unprecedented changes in today's healthcare. The expanding knowledge of the molecular basis of cancer has shown that significant differences in gene expression patterns can guide therapy not only for neoplastic conditions, but also for a variety of diseases including inflammatory disorders, cardiovascular disease and neurodegenerative processes. As a result, the fields of pharmacogenetics and pharmacogenomics have emerged as potential new testing platforms for the individualized management of patients. An individual's response to a drug is the complex interaction of both genetic and non-genetic factors. Genetic variants in the drug target itself, disease pathway genes, or drug metabolizing enzymes may all be used as predictors of drug efficacy or toxicity. In oncology, the SNP technology has focused on detecting the predisposition for cancer, predicting of toxic responses to drugs and selecting the best individual and combinations of anti-cancer drugs. Pharmacogenomics involves the application of whole genome technologies (e.g., gene and protein expression data) for the prediction of the sensitivity or resistance of an individual's disease to a single or group of drugs. Genomic microarrays and transcriptional profiling have the ability to generate hundreds of thousands of data points requiring sophisticated and complex information systems necessary for accurate and useful data analysis. This technique has generated a wealth of new information in the fields of leukemia/lymphoma, and solid tumor classification and prediction of metastasis, drug and biomarker target discovery and pharmacogenomic drug efficacy testing.
Topics: Drug Resistance, Neoplasm; Gene Expression Regulation, Neoplastic; Genetic Predisposition to Disease; Genome, Human; Humans; Neoplasms; Oligonucleotide Array Sequence Analysis; Pharmacogenetics
PubMed: 15220824
DOI: 10.1097/01.pap.0000131825.77317.ee -
Pharmacotherapy Sep 2017One of the initial steps for implementing pharmacogenomics into routine patient care is selecting an appropriate clinical laboratory to perform the testing. With the... (Review)
Review
One of the initial steps for implementing pharmacogenomics into routine patient care is selecting an appropriate clinical laboratory to perform the testing. With the rapid advances in genotyping technologies, many clinical laboratories are now performing pharmacogenomic testing. Selection of a reference laboratory depends on whether a particular genotype assay is already performed by an internal health care organization laboratory or only available externally. Other factors for consideration are coverage of genomic variants important for the patient population, technical support, and cost. In some instances, the decision to select a particular reference laboratory may be the responsibility of the clinician who is recommending genomic interrogation. Only limited guidance is available that describes the laboratory characteristics to consider when selecting a reference laboratory. We provide practical considerations for selecting a clinical laboratory for pharmacogenomic testing broadly categorized into four domains: pharmacogene and variant selection; logistics; reporting of results; and test costs along with reimbursement.
Topics: Humans; Medical Laboratory Science; Pharmacogenetics; Precision Medicine; Reference Standards
PubMed: 28699700
DOI: 10.1002/phar.1985 -
Current Topics in Medicinal Chemistry 2004Therapeutic stem cell applications represent a newly evolving approach for the treatment of several genetic and degenerative diseases. The advent of pharmacogenomics... (Review)
Review
Therapeutic stem cell applications represent a newly evolving approach for the treatment of several genetic and degenerative diseases. The advent of pharmacogenomics too, holds promise for an individualized, optimal treatment regime for a large variety of medical conditions. A combination of the benefits of these two technologies creates a new niche in therapeutic medicine research viz. that of stem cell pharmacogenomics (SCP). The development of this approach requires the application of existing technologies in genomics, proteomics and bioinformatics to resolve the various issues involved in advancing the therapeutic applications of stem cell medicine. In this brief overview of the subject, we attempt to provide fresh insights into the exclusive niche of stem cell pharmacogenomics and discuss some of the priority issues that need to be targeted, based on the existing principles of pharmacogenomics, stem cell characteristics and transplantation medicine. Advances in these areas are imperative in realizing the dream of stem cell therapies contributing towards the improvisation of the quality of human life.
Topics: Genetic Therapy; Humans; Pharmacogenetics; Stem Cell Transplantation; Stem Cells
PubMed: 15379651
DOI: 10.2174/1568026043387674 -
Pharmacotherapy Sep 2017Genotype-guided warfarin dosing algorithms are a rational approach to optimize warfarin dosing and potentially reduce adverse drug events. Diverse populations, such as... (Review)
Review
Genotype-guided warfarin dosing algorithms are a rational approach to optimize warfarin dosing and potentially reduce adverse drug events. Diverse populations, such as African Americans and Latinos, have greater variability in warfarin dose requirements and are at greater risk for experiencing warfarin-related adverse events compared with individuals of European ancestry. Although these data suggest that patients of diverse populations may benefit from improved warfarin dose estimation, the vast majority of literature on genotype-guided warfarin dosing, including data from prospective randomized trials, is in populations of European ancestry. Despite differing frequencies of variants by race/ethnicity, most evidence in diverse populations evaluates variants that are most common in populations of European ancestry. Algorithms that do not include variants important across race/ethnic groups are unlikely to benefit diverse populations. In some race/ethnic groups, development of race-specific or admixture-based algorithms may facilitate improved genotype-guided warfarin dosing algorithms above and beyond that seen in individuals of European ancestry. These observations should be considered in the interpretation of literature evaluating the clinical utility of genotype-guided warfarin dosing. Careful consideration of race/ethnicity and additional evidence focused on improving warfarin dosing algorithms across race/ethnic groups will be necessary for successful clinical implementation of warfarin pharmacogenomics. The evidence for warfarin pharmacogenomics has a broad significance for pharmacogenomic testing, emphasizing the consideration of race/ethnicity in discovery of gene-drug pairs and development of clinical recommendations for pharmacogenetic testing.
Topics: Anticoagulants; Ethnicity; Humans; Pharmacogenetics; Pharmacogenomic Variants; Polymorphism, Single Nucleotide; Warfarin
PubMed: 28672100
DOI: 10.1002/phar.1982 -
Human Molecular Genetics May 2018The field of pharmacogenomics is an area of great potential for near-term human health impacts from the big genomic data revolution. Pharmacogenomics research momentum... (Review)
Review
The field of pharmacogenomics is an area of great potential for near-term human health impacts from the big genomic data revolution. Pharmacogenomics research momentum is building with numerous hypotheses currently being investigated through the integration of molecular profiles of different cell lines and large genomic data sets containing information on cellular and human responses to therapies. Additionally, the results of previous pharmacogenetic research efforts have been formulated into clinical guidelines that are beginning to impact how healthcare is conducted on the level of the individual patient. This trend will only continue with the recent release of new datasets containing linked genotype and electronic medical record data. This review discusses key resources available for pharmacogenomics and pharmacogenetics research and highlights recent work within the field.
Topics: Big Data; Genomics; Genotype; Humans; Pharmacogenetics; Pharmacogenomic Testing
PubMed: 29635477
DOI: 10.1093/hmg/ddy116 -
Current Pharmaceutical Design 2006Patient response to asthma therapy is consistently observed to be heterogeneous. Pharmacogenomics is the study of inherited differences in interindividual drug... (Review)
Review
Patient response to asthma therapy is consistently observed to be heterogeneous. Pharmacogenomics is the study of inherited differences in interindividual drug disposition and effects, with the goal of selecting the optimal drug therapy and dosage for each patient. This review will cover selected examples of gene polymorphisms that influence the outcome of asthma therapy, and whole-genome expression studies using microarray technology that have shown tremendous potential for benefiting asthma pharmacogenomics. The utility of the mouse as an experimental system for pharmacogenomic discovery will also be discussed in the context of asthma therapy.
Topics: Animals; Anti-Asthmatic Agents; Asthma; Humans; Pharmacogenetics; Polymorphism, Genetic
PubMed: 17020528
DOI: 10.2174/138161206778194105 -
Proceedings of the Western Pharmacology... 2008Pharmacogenetics dates back more than 2,000 years to observations by Pythagoras, however it was not until the 1950s when some enzyme polymorphisms (e.g.,... (Review)
Review
Pharmacogenetics dates back more than 2,000 years to observations by Pythagoras, however it was not until the 1950s when some enzyme polymorphisms (e.g., N-acetyltransferase, G6PD) were discovered that the term was coined by Vogel. Pharmacogenetics then went into decline as being too esoteric a subject. In the 1970s the discovery of the CYP2D6 polymorphism and its resultant effect on drug toxicity and response led to many observations of pharmacogenetic-based variations in pharmacokinetics. These and other discoveries and the subsequent ability to genotype led to the term pharmacogenomics. Today, there are an increasing number of genes for which polymorphisms have been identified that are associated with variable drug response whether it be at the drug metabolizing enzyme, transporter or receptor level and, mainly through a candidate genes(s) approach. Increasing use of genome-wide analysis is identifying hitherto unpredictable new genes associated with disease and drug response. Although some old and most new drugs coming onto the market have a "pharmacogenomic footprint", the clinical and practical usefulness of pharmacogenomics has been generally lacking. To date, clinical translation of pharmacogenetics has focused on narrow therapeutic index drugs for toxicity (e.g., azathioprine) and more recently for efficacy and toxicity (e.g., warfarin) purposes. Pharmacogenetics and genomics will be advanced through lower cost, rapid whole genome sequencing methods combined with sophisticated algorithms allowing individualised dosage recommendations but not necessarily their adoption. However, complicating this is the influence of changes in gene expression by environmental and genetic factors. Therefore translation of pharmacogenetics into "personalised medicine" will depend on many factors including clinical relevance, environmental-genetic interactions, cost and education.
Topics: Drug Industry; Humans; Pharmacogenetics; Pharmacokinetics; Polymorphism, Genetic
PubMed: 19544663
DOI: No ID Found -
Implementing comprehensive pharmacogenomics in a community hospital-associated primary care setting.Journal of the American Pharmacists... 2023Pharmacogenomics (PGx) is an emerging field. Many drug-gene interactions are known but not yet routinely addressed in clinical practice. Therefore, there is a... (Review)
Review
BACKGROUND
Pharmacogenomics (PGx) is an emerging field. Many drug-gene interactions are known but not yet routinely addressed in clinical practice. Therefore, there is a significant gap in care, necessitating development of implementation strategies.
OBJECTIVE
The objective of the study was to assess the impact of implementing a PGx practice model which incorporates comprehensive pharmacogenomic risk evaluation, testing and medication optimization administered by 7 PGx-certified ambulatory care pharmacists embedded across 30 primary care clinic sites.
METHODS
Pharmacogenomic services were implemented in 30 primary care clinics within the Cincinnati, Ohio area. Patients are identified for pharmacogenomic testing using a clinical decision support tool (CDST) that is fully integrated in the electronic medical record (EMR) or by provider designation (e.g., psychotropic drug failure). Pharmacogenomic testing is performed via buccal swab using standardized clinic processes. Discrete data results are returned directly into the EMR/CDST for review by PGx-certified ambulatory care pharmacists. Recommendations and prescriptive changes are then discussed and implemented as a collaborative effort between pharmacist, primary care provider, specialists, and patient.
RESULTS
A total of 422 unique interactions were assessed by the embedded ambulatory care PGx pharmacists (N = 7) during this interim analysis. About half (213) were pharmacogenomic interactions, and of these, 124 were actionable. When an intervention was actionable, 82% of the time a change in medication was recommended. The underlying reasons for recommending therapy alterations were most commonly ineffective therapy (43%), adverse drug reaction prevented (34%), or adverse drug reaction observed (13%).
CONCLUSION
Variations in drug metabolism, response, and tolerability can negatively impact patient outcomes across many disease states and treatment specialties. Incorporation of pharmacogenomic testing with accessible clinical decision support into the team-based care model allows for a truly comprehensive review and optimization of medications. Our initial analysis suggests that comprehensive PGx testing should be considered to enhance medication safety and efficacy in at-risk patients.
Topics: Humans; Pharmacogenetics; Hospitals, Community; Pharmacogenomic Testing; Drug-Related Side Effects and Adverse Reactions; Primary Health Care
PubMed: 36243653
DOI: 10.1016/j.japh.2022.09.002