Genomic and drug target evaluation of 90 cardiovascular proteins in 30,931 individuals

Lasse Folkersen, Stefan Gustafsson, Qin Wang, Daniel Hvidberg Hansen, Åsa K Hedman, Andrew Schork, Karen Page, Daria V Zhernakova, Yang Wu, James Peters, Niclas Eriksson, Sarah E Bergen, Thibaud S Boutin, Andrew D Bretherick, Stefan Enroth, Anette Kalnapenkis, Jesper R Gådin, Bianca E Suur, Yan Chen, Ljubica MaticJeremy D Gale, Julie Lee, Weidong Zhang, Amira Quazi, Mika Ala-Korpela, Seung Hoan Choi, Annique Claringbould, John Danesh, George Davey Smith, Federico de Masi, Sölve Elmståhl, Gunnar Engström, Eric Fauman, Celine Fernandez, Lude Franke, Paul W Franks, Vilmantas Giedraitis, Chris Haley, Anders Hamsten, Andres Ingason, Åsa Johansson, Peter K Joshi, Lars Lind, Cecilia M Lindgren, Steven Lubitz, Tom Palmer, Erin Macdonald-Dunlop, Martin Magnusson, Olle Melander, Karl Michaelsson, Andrew P Morris, Reedik Mägi, Michael W Nagle, Peter M Nilsson, Jan Nilsson, Marju Orho-Melander, Ozren Polasek, Bram Prins, Erik Pålsson, Ting Qi, Marketa Sjögren, Johan Sundström, Praveen Surendran, Urmo Võsa, Thomas Werge, Rasmus Wernersson, Harm-Jan Westra, Jian Yang, Alexandra Zhernakova, Johan Ärnlöv, Jingyuan Fu, J Gustav Smith, Tõnu Esko, Caroline Hayward, Ulf Gyllensten, Mikael Landen, Agneta Siegbahn, James F Wilson, Lars Wallentin, Adam S Butterworth, Michael V Holmes, Erik Ingelsson, Anders Mälarstig

Research output: Contribution to journalArticleAcademicpeer-review

6 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1135-1148
Number of pages14
JournalNature Metabolism
Volume2
Issue number10
DOIs
Publication statusPublished - 16-Oct-2020

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