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Cell. 2018 Jan 11;172(1-2):41-54.e19. doi: 10.1016/j.cell.2017.11.033. Epub 2017 Dec 14.

Pharmacogenomics of GPCR Drug Targets.

Author information

1
MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge CB2 0QH, UK; Department of Drug Design and Pharmacology, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen, Denmark. Electronic address: alexander.hauser@sund.ku.dk.
2
MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge CB2 0QH, UK.
3
Department of Neuroscience, The Scripps Research Institute Florida, Jupiter, FL 33458, USA.
4
The Novo Nordisk Foundation Center for Biosustainability, Technical University Denmark, Kemitorvet 2800 Kgs. Lyngby, Denmark.
5
Department of Drug Design and Pharmacology, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen, Denmark.
6
MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge CB2 0QH, UK. Electronic address: madanm@mrc-lmb.cam.ac.uk.

Abstract

Natural genetic variation in the human genome is a cause of individual differences in responses to medications and is an underappreciated burden on public health. Although 108 G-protein-coupled receptors (GPCRs) are the targets of 475 (∼34%) Food and Drug Administration (FDA)-approved drugs and account for a global sales volume of over 180 billion US dollars annually, the prevalence of genetic variation among GPCRs targeted by drugs is unknown. By analyzing data from 68,496 individuals, we find that GPCRs targeted by drugs show genetic variation within functional regions such as drug- and effector-binding sites in the human population. We experimentally show that certain variants of μ-opioid and Cholecystokinin-A receptors could lead to altered or adverse drug response. By analyzing UK National Health Service drug prescription and sales data, we suggest that characterizing GPCR variants could increase prescription precision, improving patients' quality of life, and relieve the economic and societal burden due to variable drug responsiveness. VIDEO ABSTRACT.

KEYWORDS:

FDA approved drugs; GPCR; clinical trial; drug response; economic burden; natural variation; opioid receptor; personalized medicine; pharmacogenomics; polymorphism

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