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Systematic Mendelian randomization using the human plasma proteome to discover potential therapeutic targets for stroke

Author

Listed:
  • Lingyan Chen

    (University of Cambridge
    Novo Nordisk Research Centre Oxford)

  • James E. Peters

    (University of Cambridge
    Imperial College London)

  • Bram Prins

    (University of Cambridge)

  • Elodie Persyn

    (University of Cambridge
    King’s College London
    University of Cambridge)

  • Matthew Traylor

    (Novo Nordisk Research Centre Oxford
    Queen Mary University of London)

  • Praveen Surendran

    (University of Cambridge
    University of Cambridge)

  • Savita Karthikeyan

    (University of Cambridge)

  • Ekaterina Yonova-Doing

    (University of Cambridge
    Novo Nordisk Research Centre Oxford)

  • Emanuele Angelantonio

    (University of Cambridge
    University of Cambridge
    University of Cambridge
    Wellcome Genome Campus and University of Cambridge)

  • David J. Roberts

    (University of Cambridge
    John Radcliffe Hospital
    University of Oxford, John Radcliffe Hospital)

  • Nicholas A. Watkins

    (Cambridge Biomedical Campus)

  • Willem H. Ouwehand

    (University of Cambridge
    Cambridge Biomedical Campus
    University of Cambridge
    Wellcome Sanger Institute)

  • John Danesh

    (University of Cambridge
    University of Cambridge
    University of Cambridge
    Wellcome Genome Campus and University of Cambridge)

  • Cathryn M. Lewis

    (King’s College London
    King’s College London)

  • Paola G. Bronson

    (Biogen, Inc.)

  • Hugh S. Markus

    (University of Cambridge)

  • Stephen Burgess

    (University of Cambridge
    University of Cambridge
    University of Cambridge)

  • Adam S. Butterworth

    (University of Cambridge
    University of Cambridge
    University of Cambridge
    Wellcome Genome Campus and University of Cambridge)

  • Joanna M. M. Howson

    (University of Cambridge
    Novo Nordisk Research Centre Oxford)

Abstract

Stroke is the second leading cause of death with substantial unmet therapeutic needs. To identify potential stroke therapeutic targets, we estimate the causal effects of 308 plasma proteins on stroke outcomes in a two-sample Mendelian randomization framework and assess mediation effects by stroke risk factors. We find associations between genetically predicted plasma levels of six proteins and stroke (P ≤ 1.62 × 10−4). The genetic associations with stroke colocalize (Posterior Probability >0.7) with the genetic associations of four proteins (TFPI, TMPRSS5, CD6, CD40). Mendelian randomization supports atrial fibrillation, body mass index, smoking, blood pressure, white matter hyperintensities and type 2 diabetes as stroke risk factors (P ≤ 0.0071). Body mass index, white matter hyperintensity and atrial fibrillation appear to mediate the TFPI, IL6RA, TMPRSS5 associations with stroke. Furthermore, thirty-six proteins are associated with one or more of these risk factors using Mendelian randomization. Our results highlight causal pathways and potential therapeutic targets for stroke.

Suggested Citation

  • Lingyan Chen & James E. Peters & Bram Prins & Elodie Persyn & Matthew Traylor & Praveen Surendran & Savita Karthikeyan & Ekaterina Yonova-Doing & Emanuele Angelantonio & David J. Roberts & Nicholas A., 2022. "Systematic Mendelian randomization using the human plasma proteome to discover potential therapeutic targets for stroke," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-33675-1
    DOI: 10.1038/s41467-022-33675-1
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    as
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