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

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. Watkins, Willem H. Ouwehand, John Danesh, Cathryn M. Lewis, Paola G. Bronson, Hugh S. Markus, Stephen Burgess, Adam S. Butterworth and Joanna M. M. Howson ()
Additional contact information
Lingyan Chen: University of Cambridge
James E. Peters: University of Cambridge
Bram Prins: University of Cambridge
Elodie Persyn: University of Cambridge
Matthew Traylor: Novo Nordisk Research Centre Oxford
Praveen Surendran: University of Cambridge
Savita Karthikeyan: University of Cambridge
Ekaterina Yonova-Doing: University of Cambridge
Emanuele Angelantonio: University of Cambridge
David J. Roberts: University of Cambridge
Nicholas A. Watkins: Cambridge Biomedical Campus
Willem H. Ouwehand: University of Cambridge
John Danesh: University of Cambridge
Cathryn M. Lewis: King’s College London
Paola G. Bronson: Biogen, Inc.
Hugh S. Markus: University of Cambridge
Stephen Burgess: University of Cambridge
Adam S. Butterworth: University of Cambridge
Joanna M. M. Howson: University of Cambridge

Nature Communications, 2022, vol. 13, issue 1, 1-14

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-33675-1

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