Hot topic: Pharmacogenomics of GPCR Drug Targets

A system of rigorous clinical trials and regulation exist to ensure that a new drug is safe and effective when reaching the market. However, natural human genetic variation(s) may cause individuals to respond differently to the same medication. A collaboration between the MRC Laboratory of Molecular Biology, Cambridge (UK), the Scripps Research Institute in Florida and the Department of Drug Design and Pharmacology, University of Copenhagen (home of the GPCRdb team) has now published a new detailed study on the effects of genetic variation in G protein-coupled receptors on responses to FDA-approved drugs [1].

The authors address the following main questions:

• How variable are GPCR drug targets in the human population?
• Are individuals with variant receptors likely to respond differently to drugs?
• What is the estimated economic burden associated with variation in GPCR drug targets?

To address these questions, the authors have analysed datasets from multiple sources including genotype information from the 1,000 Genomes project, exome sequencing data from the exome aggregation consortium (ExAC), which contains aggregated information on genetic variants for ~60,000 ‘healthy’ individuals, structural information of receptors in complex with diverse ligands, data on functional effect of mutants and information on drug sales from the UK National Health Service.

The study reports that on average, an individual carries 68 missense variations in approximately one-third of the 108 GPCR drug targets. Many FDA approved drugs target a number of highly variable GPCRs. For example, several genetic variants for the mu-opioid receptor selected for experimental characterisation show an altered response for FDA-approved drugs, which could potentially lead to no or adverse reactions in the human population. Several variants occur within drug-binding sites and other functionally important positions, such as for the CCR5 drug-binding pocket of maraviroc, an antiretroviral drug for HIV treatment.

Based on an economic model, the authors estimated the potential economic burden due to ineffective prescribing of GPCR targeting drugs to be between 14 million and half-a-billion pounds annually in the UK alone.

This work might inspire many scientists to characterise human variants from multiple angles similar to the ENCODE project.

Key highlights:

• GPCRs targeted by FDA-approved drugs show genetic variation in the human population
• Genetic variation occurs in functional sites and may result in altered drug response
• We present an online resource of GPCR genetic variants for pharmacogenomics research
• Understanding variation in drug targets may help alleviate economic healthcare burden

(1) Hauser AS et al. (2017). Pharmacogenomics of GPCR Drug Targets. Cell, 172(1-2):41-54.e19. doi:10.1016/j.cell.2017.11.033. [PMID:29249361]

Comments by Alexander Hauser, University of Copenhagen and GPCRdb

While the above is a tour de force for GPCRs note also the genetic variation from 1K Genomes and/or ExAC can be accessed for every target protein in GtoPdb via the Ensembl gene ID we cross-reference.