Pharmacogenomics of GPCR Drug Targets

TY - JOUR

T1 - Pharmacogenomics of GPCR Drug Targets

AU - Hauser, Alexander Sebastian

AU - Chavali, Sreenivas

AU - Masuho, Ikuo

AU - Jahn, Leonie

AU - Martemyanov, Kirill

AU - Gloriam, David E.

AU - Babu, Madan

PY - 2018/1/11

Y1 - 2018/1/11

N2 - 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 [Figure presented] A pharmacogenomic analysis probes the effects of genetic variation in G-protein-coupled receptors on responses to FDA-approved drugs and estimates how this genetic variation may impact healthcare costs.

AB - 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 [Figure presented] A pharmacogenomic analysis probes the effects of genetic variation in G-protein-coupled receptors on responses to FDA-approved drugs and estimates how this genetic variation may impact healthcare costs.

U2 - 10.1016/j.cell.2017.11.033

DO - 10.1016/j.cell.2017.11.033

M3 - Journal article

C2 - 29249361

SN - 0092-8674

VL - 172

SP - 41

EP - 54

JO - Cell

JF - Cell

ER -