Editors' ChoicePharmacology

The cost of being different

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Science Signaling  27 Feb 2018:
Vol. 11, Issue 519, eaat0494
DOI: 10.1126/scisignal.aat0494

Extensive genetic variations in GPCRs may alter responses to commonly used drugs and incur a high economic burden.

About one-third of FDA-approved drugs target G protein–coupled receptors (GPCRs). Hauser et al. estimated the prevalence, location, effect, and economic burden of genetic variations in 108 GPCR-encoding genes that affect drug responses. Analysis of the 1000 Genomes Project and exome aggregation consortium (ExAC) revealed that genes encoding GPCRs showed genetic variability, such as missense, loss-of-function, and copy-number variations. Furthermore, based on crystal structure data, many of these genetic variations were predicted to have a functional impact. The authors characterized the potential effect of genetic variations on drug responses for various drug-targeted GPCRs, including the μ-opioid receptor. BRET analysis of variants with uncharacterized polymorphisms around the ligand-binding site showed that two variants had altered responses to synthetic opioids but not to the endogenous ligand or morphine, whereas naloxone (which can reverse opioid overdose because it is an antagonist for opioid receptors) did not act as a full antagonist for two gain-of-function variants. Thus, naloxone would be less effective at saving individuals with either of these two gain-of-function variants from opioid overdoses. The authors estimated a high economic burden in the United Kingdom due to genetic variation for 279 GPCR-targeting drugs. The extensive prevalence of GPCR variants, combined with their potential effect on drug responses and associated health costs, suggest that clinically relevant genetic variants need to be taken into account when assessing the efficacy and side effect profile of GPCR-targeting drugs.

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