Journal Article

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

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

2020

Overview

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. Folkersen et al. report the first results from the SCALLOP consortium, a collaborative framework for pQTL mapping and biomarker analysis of proteins on the Olink platform. A total of 315 primary and 136 secondary pQTLs for 85 circulating cardiovascular proteins from over 30,000 individuals were identified and replicated to yield new insights for translational studies and drug development.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 45/61 / 631/208/212 / 631/337/475 / 692/4017 / 82/79 / ABCA1 protein / Asthma - genetics / ATP Binding Cassette Transporter 1 - genetics / ATP-binding protein / Basic Medicine / Biomarkers / Biomedical and Life Sciences / Cardiology and Cardiovascular Disease / Cardiovascular System - metabolism / CC chemokine receptors / Chemokine receptors / Chromosome Mapping / Clinical Medicine / CXCL16 protein / Decision making / Drug Delivery Systems / Drug development / Gene expression / Gene Knockdown Techniques / Gene loci / Gene mapping / Genome-Wide Association Study / Genomes / Genomics / Humans / Hypotheses / Inflammatory Bowel Diseases - genetics / Interleukin-1 Receptor-Like 1 Protein - genetics / Intracellular Signaling Peptides and Proteins - genetics / Kardiologi och kardiovaskulära sjukdomar / Klinisk medicin / Life Sciences / Linkage Disequilibrium / Medical and Health Sciences / Medical Genetics and Genomics (including Gene Therapy) / Medicin och hälsovetenskap / Medicinsk genetik och genomik (Här ingår: Genterapi) / Medicinska och farmaceutiska grundvetenskaper / Mendelian Randomization Analysis / Meta-analysis / Non-pharmacological intervention / Peptide mapping / Plasma / Protein Serine-Threonine Kinases - antagonists & inhibitors / Protein Serine-Threonine Kinases - genetics / Proteins / Proteome / Proteomes / Psychiatry / Psykiatri / Quantitative Trait Loci / Receptors, CCR2 - genetics / Receptors, CCR5 - genetics / Therapeutic targets