Pharmacogenomics of GPCR Drug Targets

Abstract

SummaryNatural 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

GPCRmd uncovers the dynamics of the 3D-GPCRome

“…4B). To account for the fact that almost 25% of the GPCR functional sites show an average of at least one polymorphism, we mapped all GPCR variants 25 and site-directed mutations 26 from the GPCRdb 4 to each GPCR structure. Flexible options allow users to change the color of the map type (classical fo-fc or composite 2fo-fc), style (e.g.…”

Clinical genetic testing in endocrinology: Current concepts and contemporary challenges

“…117 Furthermore, recent studies indicate considerable genetic variation in drug-targeting sites of many G-protein coupled receptors (GPCRs), which may provide an area of furtive research for the endocrine field. 118 Likewise, another recent study demonstrated asthma patients carrying specific genetic variants in the PDGFR gene were at increased risk of steroid-induced adrenal suppression. 119 Thus, it is possible that genetic testing may not only be used to guide therapy but also to predict those at increased risk of adverse endocrine outcomes.…”

“…Other emerging areas for genetic testing include pharmacogenomic assays to identify individuals with enhanced, reduced or adverse responses to specific therapies (eg association of aminoglycoside ototoxicity with a mitochondrial DNA mutation) . Furthermore, recent studies indicate considerable genetic variation in drug‐targeting sites of many G‐protein coupled receptors (GPCRs), which may provide an area of furtive research for the endocrine field . Likewise, another recent study demonstrated asthma patients carrying specific genetic variants in the PDGFR gene were at increased risk of steroid‐induced adrenal suppression .…”

Toward Dynamic Prescribing Information: Codevelopment of Companion Model‐Informed Precision Dosing Tools in Drug Development

“…When dose adjustment occurs, it is usually based on a single covariate such as body weight (eg, low‐molecular‐weight heparins) or renal function (eg, oseltamivir) . However, our understanding of PK/PD now goes beyond these simple covariates in the PI to include the “unseen” physiological and molecular determinants of drug disposition and response—DMET activities, organ sizes and blood flows, inflammatory status, gut microbiome, genetics of molecular targets, and so forth . The word unseen is used here because such covariates are either not currently tested for in clinical practice, or if they are tested for, most doctors are unclear about how to action the result, such as pharmacogenomic test results for DMETs, that is, the prescriber is literally blind to their importance.…”