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

Research output: Contribution to journalArticle

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.

Details

Authors
Organisations
External organisations
  • Wellcome Trust Centre for Human Genetics
  • Uppsala University
  • Danish National Genome Center
  • University of Oulu
  • Intomics A/S
  • Karolinska Institutet
  • Pfizer Limited, UK
  • The Translational Genomics Research Institute
  • Pfizer Worldwide Research, Cambridge Ma.
  • University of Groningen
  • University of Cambridge
  • Imperial College London
  • University of Edinburgh
  • Karolinska University Hospital
  • Skåne University Hospital
  • University of Queensland
  • SCALLOP consortium.
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Medical Genetics
  • Cardiac and Cardiovascular Systems
Original languageEnglish
Pages (from-to)1135-1148
Number of pages14
JournalNature Metabolism
Volume2
Issue number10
Publication statusPublished - 2020 Oct
Publication categoryResearch
Peer-reviewedYes

Bibliographic note

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