Pharmacogenomics of GPCR Drug Targets.
Pharmacogenomics of GPCR Drug Targets.
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DOI：
10.1016/j.cell.2017.11.033
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发表时间：
2018-01-11
期刊：
影响因子：
64.5
通讯作者：
Babu MM
中科院分区：
文献类型：
--
作者：
Hauser AS;Chavali S;Masuho I;Jahn LJ;Martemyanov KA;Gloriam DE;Babu MM
人类基因组中的自然遗传变异是对药物反应的个体差异的原因，也是公共卫生的一个未被充分认识的负担。尽管108种G蛋白偶联受体（GPCR）是475种（约34%）美国食品药品监督管理局（FDA）批准的药物的靶点，并且占全球每年超过1800亿美元的销售额，但是药物靶向的GPCR中遗传变异的流行率是未知的。通过分析来自68，496名个体的数据，我们发现药物靶向的GPCR显示出功能区域内的遗传变异，例如人类群体中的药物和效应器结合位点。我们的实验表明，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。通过分析英国国家卫生服务局的药物处方和销售数据，我们认为，表征GPCR变异可以提高处方精度，改善患者的生活质量，并减轻由于药物反应性变化而造成的经济和社会负担。FDA批准的药物靶向的GPCR显示了人群中的遗传变异遗传变异发生在功能位点，可能导致药物反应改变我们为药物基因组学研究提供了GPCR遗传变异的在线资源了解药物靶点的变异可能有助于减轻经济医疗负担药物基因组学分析探讨了G蛋白偶联受体的遗传变异对FDA反应的影响-批准的药物，并估计这种遗传变异如何影响医疗保健费用。
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. GPCRs targeted by FDA-approved drugs show genetic variation in the human population Genetic variation occurs in functional sites and may result in altered drug response We present an online resource of GPCR genetic variants for pharmacogenomics research Understanding variation in drug targets may help alleviate economic healthcare burden 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.
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Arpeggio：用于计算和可视化蛋白质结构中原子间相互作用的Web服务器。
影响因子：
5.6
作者：
Jubb HC;Higueruelo AP;Ochoa-Montaño B;Pitt WR;Ascher DB;Blundell TL
通讯作者：
Blundell TL
影响因子：
64.8
作者：
Kang Y;Zhou XE;Gao X;He Y;Liu W;Ishchenko A;Barty A;White TA;Yefanov O;Han GW;Xu Q;de Waal PW;Ke J;Tan MH;Zhang C;Moeller A;West GM;Pascal BD;Van Eps N;Caro LN;Vishnivetskiy SA;Lee RJ;Suino-Powell KM;Gu X;Pal K;Ma J;Zhi X;Boutet S;Williams GJ;Messerschmidt M;Gati C;Zatsepin NA;Wang D;James D;Basu S;Roy-Chowdhury S;Conrad CE;Coe J;Liu H;Lisova S;Kupitz C;Grotjohann I;Fromme R;Jiang Y;Tan M;Yang H;Li J;Wang M;Zheng Z;Li D;Howe N;Zhao Y;Standfuss J;Diederichs K;Dong Y;Potter CS;Carragher B;Caffrey M;Jiang H;Chapman HN;Spence JC;Fromme P;Weierstall U;Ernst OP;Katritch V;Gurevich VV;Griffin PR;Hubbell WL;Stevens RC;Cherezov V;Melcher K;Xu HE
通讯作者：
Xu HE
影响因子：
4.8
作者：
Hollins B;Kuravi S;Digby GJ;Lambert NA
通讯作者：
Lambert NA
影响因子：
14.9
作者：
Huang KY;Su MG;Kao HJ;Hsieh YC;Jhong JH;Cheng KH;Huang HD;Lee TY
通讯作者：
Lee TY
DOI：
10.1038/nrd.2017.178
发表时间：
2017-12
期刊：
Nature reviews. Drug discovery
影响因子：
--
作者：
Hauser AS;Attwood MM;Rask-Andersen M;Schiöth HB;Gloriam DE
通讯作者：
Gloriam DE