Pharmacogenomics of GPCR Drug Targets

TLDR

Natural genetic variation in the human genome contributes to individual drug response differences and represents an underappreciated public health burden, yet the prevalence of variation in the 108 GPCRs that target 475 FDA‑approved drugs and generate over $180 billion in sales remains unknown. The study aims to show that profiling GPCR variants using NHS prescription and sales data could enhance prescription precision, improve patient quality of life, and reduce economic and societal burdens from variable drug responsiveness. The authors analyzed genetic data from 68,496 individuals to identify functional variation in drug‑ and effector‑binding sites of GPCRs targeted by drugs. The study demonstrates that drug‑targeted GPCRs harbor functional genetic variation, that specific μ‑opioid and Cholecystokinin‑A receptor variants can alter drug response, and that profiling these variants using NHS prescription data could improve prescription precision and reduce societal burden.

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.