MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge CB2 0QH, UK; Department of Drug Design and Pharmacology, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen, Denmark.
MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge CB2 0QH, UK.
Cell. 2018 Jan 11;172(1-2):41-54.e19. doi: 10.1016/j.cell.2017.11.033. Epub 2017 Dec 14.
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.
人类基因组中的自然遗传变异是导致药物反应个体差异的原因，也是公共卫生领域未被充分重视的负担。尽管 108 个 G 蛋白偶联受体（GPCR）是 475 种（约 34%）获得美国食品和药物管理局（FDA）批准的药物的靶点，每年的全球销售额超过 1800 亿美元，但药物作用靶点 GPCR 中的遗传变异的普遍性尚不清楚。通过分析来自 68496 个人的数据，我们发现药物作用靶点的 GPCR 在人类群体中存在功能区域（如药物和效应物结合位点）的遗传变异。我们通过实验表明，μ-阿片受体和胆囊收缩素 A 受体的某些变体可能导致药物反应的改变或不良反应。通过分析英国国家医疗服务体系的药物处方和销售数据，我们认为鉴定 GPCR 变体可以提高药物的处方精度，改善患者的生活质量，并减轻由于药物反应性不同而带来的经济和社会负担。视频摘要。
