Genomic and drug target evaluation of 90 cardiovascular proteins in 30,931 individuals.
Genomic and drug target evaluation of 90 cardiovascular proteins in 30,931 individuals.
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DOI：
10.1038/s42255-020-00287-2
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发表时间：
2020-10
影响因子：
20.8
通讯作者：
Mälarstig A
中科院分区：
文献类型：
--
作者：
Folkersen L;Gustafsson S;Wang Q;Hansen DH;Hedman ÅK;Schork A;Page K;Zhernakova DV;Wu Y;Peters J;Eriksson N;Bergen SE;Boutin TS;Bretherick AD;Enroth S;Kalnapenkis A;Gådin JR;Suur BE;Chen Y;Matic L;Gale JD;Lee J;Zhang W;Quazi A;Ala-Korpela M;Choi SH;Claringbould A;Danesh J;Davey Smith G;de Masi F;Elmståhl S;Engström G;Fauman E;Fernandez C;Franke L;Franks PW;Giedraitis V;Haley C;Hamsten A;Ingason A;Johansson Å;Joshi PK;Lind L;Lindgren CM;Lubitz S;Palmer T;Macdonald-Dunlop E;Magnusson M;Melander O;Michaelsson K;Morris AP;Mägi R;Nagle MW;Nilsson PM;Nilsson J;Orho-Melander M;Polasek O;Prins B;Pålsson E;Qi T;Sjögren M;Sundström J;Surendran P;Võsa U;Werge T;Wernersson R;Westra HJ;Yang J;Zhernakova A;Ärnlöv J;Fu J;Smith JG;Esko T;Hayward C;Gyllensten U;Landen M;Siegbahn A;Wilson JF;Wallentin L;Butterworth AS;Holmes MV;Ingelsson E;Mälarstig A
循环蛋白对人类健康和疾病至关重要，经常被用作临床决策的生物标志物或作为药物干预的靶点。在这里，我们在30,000多个个体中绘制并复制了90种心血管蛋白的蛋白质数量性状位点（pQTL），得到85种蛋白质的451个pQTL。对于每个蛋白，我们进一步进行通路定位以获得trans-pQTL基因和调控指定。通过小鼠敲除实验（ABCA1, TRIB1）和临床试验结果（CCR2, CCR5），我们用正交证据证实了这些调控发现，这些发现具有一致的调控作用。最后，我们评估已知的药物靶点，并建议新的靶点候选或重新定位机会使用孟德尔随机化。该研究确定了11种与人类疾病有因果关系的蛋白，包括（基因符号）EGF、IL16、PAPPA、SPON1、F3、ADM、CASP8、CHI3L1、CXCL16、GDF15和MMP12。综上所述，这些发现证明了大规模绘制蛋白质组遗传图谱的实用性，并为未来对人类健康循环蛋白的精确研究提供了资源。
Circulating proteins are vital in human health and disease and are frequently used as biomarkers for clinical decision-making or as targets for pharmacological intervention. Here we map and replicate protein quantitative trait loci (pQTL) for 90 cardiovascular proteins in over 30,000 individuals, resulting in 451 pQTLs for 85 proteins. For each protein we further perform pathway mapping to obtain trans-pQTL gene and regulatory designations. We substantiate these regulatory findings with orthogonal evidence for trans-pQTLs using mouse knock-down experiments (ABCA1, TRIB1) and clinical trial results (CCR2, CCR5), with consistent regulation. Finally we evaluate known drug targets, and suggest new target candidates or repositioning opportunities using Mendelian randomization. This identifies 11 proteins with causal evidence of involvement in human disease that have not previously been targeted, including (gene symbols) EGF, IL16, PAPPA, SPON1, F3, ADM, CASP8, CHI3L1, CXCL16, GDF15, and MMP12. Taken together these findings demonstrate the utility of large-scale mapping the genetics of the proteome, and provide a resource for future precision studies of circulating proteins in human health.
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影响因子：
4.5
作者：
Melzer D;Perry JR;Hernandez D;Corsi AM;Stevens K;Rafferty I;Lauretani F;Murray A;Gibbs JR;Paolisso G;Rafiq S;Simon-Sanchez J;Lango H;Scholz S;Weedon MN;Arepalli S;Rice N;Washecka N;Hurst A;Britton A;Henley W;van de Leemput J;Li R;Newman AB;Tranah G;Harris T;Panicker V;Dayan C;Bennett A;McCarthy MI;Ruokonen A;Jarvelin MR;Guralnik J;Bandinelli S;Frayling TM;Singleton A;Ferrucci L
通讯作者：
Ferrucci L
影响因子：
64.8
作者：
Bycroft C;Freeman C;Petkova D;Band G;Elliott LT;Sharp K;Motyer A;Vukcevic D;Delaneau O;O'Connell J;Cortes A;Welsh S;Young A;Effingham M;McVean G;Leslie S;Allen N;Donnelly P;Marchini J
通讯作者：
Marchini J
遗传对人体组织基因表达的影响。
影响因子：
64.8
作者：
GTEx Consortium;Laboratory, Data Analysis &Coordinating Center (LDACC)—Analysis Working Group;Statistical Methods groups—Analysis Working Group;Enhancing GTEx (eGTEx) groups;NIH Common Fund;NIH/NCI;NIH/NHGRI;NIH/NIMH;NIH/NIDA;Biospecimen Collection Source Site—NDRI;Biospecimen Collection Source Site—RPCI;Biospecimen Core Resource—VARI;Brain Bank Repository—University of Miami Brain Endowment Bank;Leidos Biomedical—Project Management;ELSI Study;Genome Browser Data Integration &Visualization—EBI;Genome Browser Data Integration &Visualization—UCSC Genomics Institute, University of California Santa Cruz;Lead analysts:;Laboratory, Data Analysis &Coordinating Center (LDACC):;NIH program management:;Biospecimen collection:;Pathology:;eQTL manuscript working group:;Battle A;Brown CD;Engelhardt BE;Montgomery SB
通讯作者：
Montgomery SB
影响因子：
30.8
作者：
Bulik-Sullivan, Brendan K.;Loh, Po-Ru;Finucane, Hilary K.;Ripke, Stephan;Yang, Jian;Patterson, Nick;Daly, Mark J.;Price, Alkes L.;Neale, Benjamin M.
通讯作者：
Neale, Benjamin M.
影响因子：
20.3
作者：
Nishimoto, Norihiro;Terao, Kimio;Kakehi, Takahiro
通讯作者：
Kakehi, Takahiro