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

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T1 - Genomic and drug target evaluation of 90 cardiovascular proteins in 30,931 individuals

AU - Folkersen, Lasse

AU - Gustafsson, Stefan

AU - Wang, Qin

AU - Hansen, Daniel Hvidberg

AU - Hedman, Åsa K

AU - Schork, Andrew

AU - Page, Karen

AU - Zhernakova, Daria V

AU - Wu, Yang

AU - Peters, James

AU - Eriksson, Niclas

AU - Bergen, Sarah E

AU - Boutin, Thibaud S

AU - Bretherick, Andrew D

AU - Enroth, Stefan

AU - Kalnapenkis, Anette

AU - Gådin, Jesper R

AU - Suur, Bianca E

AU - Chen, Yan

AU - Matic, Ljubica

AU - Gale, Jeremy D

AU - Lee, Julie

AU - Zhang, Weidong

AU - Quazi, Amira

AU - Ala-Korpela, Mika

AU - Choi, Seung Hoan

AU - Claringbould, Annique

AU - Danesh, John

AU - Davey Smith, George

AU - de Masi, Federico

AU - Elmståhl, Sölve

AU - Engström, Gunnar

AU - Fauman, Eric

AU - Fernandez, Celine

AU - Franke, Lude

AU - Franks, Paul W

AU - Giedraitis, Vilmantas

AU - Haley, Chris

AU - Hamsten, Anders

AU - Ingason, Andres

AU - Johansson, Åsa

AU - Lindgren, Cecilia M

AU - Magnusson, Martin

AU - Melander, Olle

AU - Nilsson, Peter M

AU - Nilsson, Jan

AU - Orho-Melander, Marju

AU - Sjögren, Marketa

AU - Yang, Jian

AU - Wallentin, Lars

AU - SCALLOP Consortium

N1 - These authors contributed equally: Lasse Folkersen, Stefan Gustafsson, Qin Wang, Michael V. Holmes, Erik Ingelsson, Anders Mälarstig

PY - 2020/10

Y1 - 2020/10

N2 - 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.

AB - 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.

U2 - 10.1038/s42255-020-00287-2

DO - 10.1038/s42255-020-00287-2

M3 - Article

C2 - 33067605

VL - 2

SP - 1135

EP - 1148

JO - Nature Metabolism

JF - Nature Metabolism

SN - 2522-5812

IS - 10

ER -