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

Folkersen, Lasse ; Gustafsson, Stefan LU ; Wang, Qin ; Hansen, Daniel Hvidberg ; Hedman, Åsa K ; Schork, Andrew ; Page, Karen ; Zhernakova, Daria V ; Wu, Yang and Peters, James , et al. (2020) In Nature Metabolism 2(10). p.1135-1148
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... (More)

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.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Nature Metabolism
volume
2
issue
10
pages
14 pages
publisher
Springer Nature
external identifiers
  • pmid:33067605
  • scopus:85092730095
ISSN
2522-5812
DOI
10.1038/s42255-020-00287-2
language
English
LU publication?
yes
additional info
These authors contributed equally: Lasse Folkersen, Stefan Gustafsson, Qin Wang, Michael V. Holmes, Erik Ingelsson, Anders Mälarstig
id
9a451a80-186c-48e3-984d-ad6861a35aa6
date added to LUP
2020-10-22 10:28:08
date last changed
2021-05-19 02:18:53
@article{9a451a80-186c-48e3-984d-ad6861a35aa6,
  abstract     = {<p>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.</p>},
  author       = {Folkersen, Lasse and Gustafsson, Stefan and Wang, Qin and Hansen, Daniel Hvidberg and Hedman, Åsa K and Schork, Andrew and Page, Karen and Zhernakova, Daria V and Wu, Yang and Peters, James and Eriksson, Niclas and Bergen, Sarah E and Boutin, Thibaud S and Bretherick, Andrew D and Enroth, Stefan and Kalnapenkis, Anette and Gådin, Jesper R and Suur, Bianca E and Chen, Yan and Matic, Ljubica and Gale, Jeremy D and Lee, Julie and Zhang, Weidong and Quazi, Amira and Ala-Korpela, Mika and Choi, Seung Hoan and Claringbould, Annique and Danesh, John and Davey Smith, George and de Masi, Federico and Elmståhl, Sölve and Engström, Gunnar and Fauman, Eric and Fernandez, Celine and Franke, Lude and Franks, Paul W and Giedraitis, Vilmantas and Haley, Chris and Hamsten, Anders and Ingason, Andres and Johansson, Åsa and Lindgren, Cecilia M and Magnusson, Martin and Melander, Olle and Nilsson, Peter M and Nilsson, Jan and Orho-Melander, Marju and Sjögren, Marketa and Yang, Jian and Wallentin, Lars},
  issn         = {2522-5812},
  language     = {eng},
  number       = {10},
  pages        = {1135--1148},
  publisher    = {Springer Nature},
  series       = {Nature Metabolism},
  title        = {Genomic and drug target evaluation of 90 cardiovascular proteins in 30,931 individuals},
  url          = {http://dx.doi.org/10.1038/s42255-020-00287-2},
  doi          = {10.1038/s42255-020-00287-2},
  volume       = {2},
  year         = {2020},
}