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Olle Melander

Principal investigator

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

Author

  • 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 Matic
  • Jeremy 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
  • Cecilia M Lindgren
  • Martin Magnusson
  • Olle Melander
  • Peter M Nilsson
  • Jan Nilsson
  • Marju Orho-Melander
  • Marketa Sjögren
  • Gustav Smith
  • Jian Yang
  • Lars Wallentin

Summary, in English

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.

Department/s

  • Geriatrics
  • EpiHealth: Epidemiology for Health
  • Cardiovascular Research - Epidemiology
  • Cardiovascular Research - Hypertension
  • EXODIAB: Excellence in Diabetes Research in Sweden
  • Genetic and Molecular Epidemiology
  • WCMM-Wallenberg Centre for Molecular Medicine
  • Internal Medicine - Epidemiology
  • Cardiovascular Research - Immunity and Atherosclerosis
  • Diabetes - Cardiovascular Disease
  • Cardiology
  • Molecular Epidemiology and Cardiology

Publishing year

2020-10

Language

English

Pages

1135-1148

Publication/Series

Nature Metabolism

Volume

2

Issue

10

Document type

Journal article

Publisher

Springer Nature

Topic

  • Medical Genetics
  • Cardiac and Cardiovascular Systems

Status

Published

Research group

  • Geriatrics
  • Cardiovascular Research - Epidemiology
  • Cardiovascular Research - Hypertension
  • Genetic and Molecular Epidemiology
  • Internal Medicine - Epidemiology
  • Cardiovascular Research - Immunity and Atherosclerosis
  • Diabetes - Cardiovascular Disease
  • Molecular Epidemiology and Cardiology

ISBN/ISSN/Other

  • ISSN: 2522-5812