| Literature DB >> 33067605 |
Lasse Folkersen1,2,3, Stefan Gustafsson3,4, Qin Wang3,5,6, Michael V Holmes3,7,8, Erik Ingelsson3,9, Anders Mälarstig10,11,12, Daniel Hvidberg Hansen3,13, Åsa K Hedman1,3,14, Andrew Schork3,15,16, Karen Page3,17, Daria V Zhernakova3,18, Yang Wu3,19, James Peters3,20,21,22, Niclas Eriksson3,23, Sarah E Bergen3,24, Thibaud S Boutin3,25, Andrew D Bretherick3,25, Stefan Enroth3,26, Anette Kalnapenkis3,27,28, Jesper R Gådin1,3, Bianca E Suur3,29, Yan Chen1,3, Ljubica Matic3,29, Jeremy D Gale3,30, Julie Lee3,17, Weidong Zhang3,31, Amira Quazi3,17, Mika Ala-Korpela3,5,6,32, Seung Hoan Choi3,33, Annique Claringbould3,18, John Danesh3,20,21,34,35,36,37, George Davey Smith3,38, Federico de Masi3,13, Sölve Elmståhl3,39, Gunnar Engström3,39, Eric Fauman3,40, Celine Fernandez3,39, Lude Franke3,18, Paul W Franks3,41, Vilmantas Giedraitis3,42, Chris Haley3,25, Anders Hamsten1,3, Andres Ingason3,15, Åsa Johansson3,26, Peter K Joshi3,43, Lars Lind3,44, Cecilia M Lindgren3,33,45,46, Steven Lubitz3,33,47, Tom Palmer3,48, Erin Macdonald-Dunlop3,43, Martin Magnusson3,49,50,51, Olle Melander3,39, Karl Michaelsson3,52, Andrew P Morris3,46,53,54, Reedik Mägi3,27, Michael W Nagle3,40, Peter M Nilsson3,39, Jan Nilsson3,39, Marju Orho-Melander3,55, Ozren Polasek3,56, Bram Prins3,20,21, Erik Pålsson3,57, Ting Qi3,19, Marketa Sjögren3,39, Johan Sundström3,58,59, Praveen Surendran3,20,21,34,60, Urmo Võsa3,27, Thomas Werge3,15, Rasmus Wernersson3,13, Harm-Jan Westra3,18, Jian Yang3,19,61,62, Alexandra Zhernakova3,18, Johan Ärnlöv3,63, Jingyuan Fu3,18,64, J Gustav Smith3,50,65, Tõnu Esko3,27,33, Caroline Hayward3,25, Ulf Gyllensten3,26, Mikael Landen3,57, Agneta Siegbahn3,66, James F Wilson3,25,43, Lars Wallentin3,67, Adam S Butterworth3,20,21,34,35,36.
Abstract
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 knockdown experiments (ABCA1 and TRIB1) and clinical trial results (chemokine receptors CCR2 and 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 EGF, IL-16, PAPPA, SPON1, F3, ADM, CASP-8, CHI3L1, CXCL16, GDF15 and MMP-12. Taken together, these findings demonstrate the utility of large-scale mapping of the genetics of the proteome and provide a resource for future precision studies of circulating proteins in human health.Entities:
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Year: 2020 PMID： 33067605 PMCID： PMC7611474 DOI： 10.1038/s42255-020-00287-2
Source DB: PubMed Journal: Nat Metab ISSN： 2522-5812