Using systems approaches to address challenges for clinical implementation of pharmacogenomics

Karnes, Jason H.; Driest, Sara L. Van; Bowton, Erica; Weeke, Peter; Mosley, Jonathan D.; Peterson, Josh F.; Denny, Joshua C.; Roden, Dan M.

doi:10.1002/wsbm.1255

Cited by 19 publications

(16 citation statements)

References 55 publications

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“…These groups cite the incorporation of renal dose adjustments in clinical care and a slew of other clinical adjustments that are not supported by RCTs. An RCT for personalized medicine can be seen as a contradiction in terms, in that a randomized treatment structure is applied to personalized care . Opponents of this view maintain the central requirement of RCT level evidence in clinical decision making.…”

Section: Future Directionsmentioning

confidence: 99%

Warfarin Pharmacogenomics in Diverse Populations

et al. 2017

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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 warfarinrelated 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.

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Section: Future Directionsmentioning

confidence: 99%

Warfarin Pharmacogenomics in Diverse Populations

et al. 2017

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“…The authors concluded that the α 2c AR 322–325Del allele in combination with bucindolol resulted in excessive NA lowering, which in the presence of the low NA affinity β‐AR (Gly389) led to insufficient levels of NA to maintain the myocardium in heart failure . The same polymorphisms, ADRB1 Arg389Gly and ADRAC2 Ins322–325Del, have also been shown to differentiate the risks for ventricular arrhythmias (interaction test; P = 0.028) and new onset atrial fibrillation (interaction test; P = 0.016) between bucindolol and placebo in the BEST genetic cohort . Although these data are encouraging for reintroduction of bucindolol to clinical practice, there remains a need for prospective randomized genotyping studies.…”

Section: Pharmacogenetic Rescue Of Failed Therapiesmentioning

confidence: 99%

“…Our lack of understanding of this complex network of interactions leads to unexpected drug ineffectiveness and adverse drug reactions. Systems approaches aim to look at the complete network, which could be a single cell, individual, or population, by utilizing data from a multitude of biological sources (e.g., genomics, transcriptomics, phenotypes, proteomics, electronic medical records) to generate descriptive models that accurately describe the complex interactions in a system (e.g., drug response, disease pathophysiology) . Interactions and common functions between the different information sources are incorporated into the system, which is visualized and refined iteratively, enabling scientists and clinicians to predict phenotype effects when part of the system is perturbed (e.g., administration of medication) .…”

Section: Systems Approaches In Pharmacogeneticsmentioning

confidence: 99%

Pharmacogenetic Markers of Drug Efficacy and Toxicity

Yip

Hawcutt

Pirmohamed

2015

Clin Pharma and Therapeutics

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The action of a drug is dictated by its pharmacokinetic and pharmacodynamics properties, both of which can vary in different individuals because of environmental and genetic factors. Pharmacogenetics, the study of genetic factors determining drug response, has the potential to improve clinical outcomes through targeting therapies, individualizing dosing, preventing adverse drug reactions, and potentially rescuing previously failed therapies. Although there have been significant advances in pharmacogenetics over the last decade, only a few have been translated into clinical practice. However, with new rapid genotyping technologies, regulatory modernization, novel clinical trial designs, systems approaches, and integration of pharmacogenetic data into decision support systems, there is hope that pharmacogenetics, as an important component of the overall drive towards personalized medicine, will advance more quickly in the future. There will continue to be a need for collaboration between centers all over the world, and multisector working, capitalizing on the current data revolution.

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“…Analysis of the effects of multiple genetic variants may require very large data sets and may be facilitated by complementary ‘omics’ data including metabolomic, transcriptomic and proteomic profiling. 11 …”

Section: Classes Of Genes Modulating Drug Actionmentioning

confidence: 99%

Cardiovascular pharmacogenomics: current status and future directions

Roden

2015

J Hum Genet

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Drugs are widely used and highly effective in the treatment of heart disease. Nevertheless, in some instances, even drugs effective in a population display lack of efficacy or adverse drug reactions in individual patients, often in an apparently unpredictable fashion. This review summarizes the genomic factors now known to influence variability in responses to widely used cardiovascular drugs such as clopidogrel, warfarin, heparin and statins. Genomic approaches being used to discover new pathways in common cardiovascular diseases and thus potential new targets for drug development are described. Finally, the way in which this new information is likely to be used in an electronic medical record environment is discussed.

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Using systems approaches to address challenges for clinical implementation of pharmacogenomics

Cited by 19 publications

References 55 publications

Warfarin Pharmacogenomics in Diverse Populations

Warfarin Pharmacogenomics in Diverse Populations

Pharmacogenetic Markers of Drug Efficacy and Toxicity

Cardiovascular pharmacogenomics: current status and future directions

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