Abstract
Introduction
The initial decades of the twenty-first century have witnessed striking technical advances that have made it possible to detect, identify and quantitatively measure large numbers of plasma or tissue metabolites. In parallel, similar advances have taken place in our ability to sequence DNA and RNA. Those advances have moved us beyond studies of single metabolites and single genetic polymorphisms to the study of hundreds or thousands of metabolites and millions of genomic variants in a single cell or subject. It is now possible to merge and integrate large data sets generated by the use of different “-omics” techniques to increase our understanding of the molecular basis for variation in disease risk and/or drug response phenotypes.
Objectives
This “Brief Review” will outline some of the challenges and opportunities associated with studies in which metabolomic data have been merged with genomics in an attempt to gain novel insight into mechanisms associated with variation in drug response phenotypes, with an emphasis on the application of a pharmacometabolomics-informed pharmacogenomic research strategy and with selected examples of the application of that strategy.
Methods
Studies that used pharmacometabolomics to inform and guide pharmacogenomics were reviewed. Clinical studies that were used as the basis for pharmacometabolomics-informed pharmacogenomic studies, published in five independent manuscripts, are described briefly.
Results
Within these five manuscripts, both pharmacokinetic and pharmacodynamic metabolomics approaches were used. Candidate gene and genome-wide approaches that were used in concert with these metabolomic data identified novel metabolite-gene relationships that were associated with drug response phenotypes in these pharmacometabolomics-informed pharmacogenomics studies.
Conclusion
This “Brief Review” outlines the emerging discipline of pharmacometabolomics-informed pharmacogenomics in which metabolic profiles are associated with both clinical phenotypes and genetic variants to identify novel genetic variants associated with drug response phenotypes based on metabolic profiles.
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Funding
This work was supported, in part, by U19 GM61388 (the Pharmacogenomics Research Network), RO1 GM28157 and by R24 GM078233 (The Metabolomics Research Network for Drug Response Phenotype) and by RC2 GM092729 (The Metabolomics Network for Drug Response Phenotype).
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All the patients included in the studies described in this review were reported to have provided informed consent for their participation in the original research.
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Neavin, D., Kaddurah-Daouk, R. & Weinshilboum, R. Pharmacometabolomics informs pharmacogenomics. Metabolomics 12, 121 (2016). https://doi.org/10.1007/s11306-016-1066-x
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DOI: https://doi.org/10.1007/s11306-016-1066-x