Pharmacogenomics of GPCR Drug Targets

By Alexander S. Hauser, S. Chavali, Ikuo Masuho, L. Jahn, K. Martemyanov, David E. Gloriam, M. Babu. 2018

545 citations recorded by the source corpus.

Summary 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

Subfields: Endocrinology, Diabetes and Metabolism, Molecular Biology, Pharmacology

Citations in the corpus

• Simulation-assisted machine learning (2018, neutral): “Although in a small fraction of cases specific genetic conditions are used to guide therapy choices, for example breast (commonly amplified gene: HER2), melanoma (BRAF mutation), lung (EML4-ALK fusion), and head-and-neck (HPV status for radiation dose de-escalation (Mirghani and Blanchard, 2017)), t”