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 Di 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; Joanna M.M. Howson

doi:10.1038/s41467-022-33675-1

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 Di 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, Joanna M.M. Howson^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

64 Citations (Scopus)

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.

Original language	English
Article number	6143
Journal	Nature Communications
Volume	13
Issue number	1
DOIs	https://doi.org/10.1038/s41467-022-33675-1
Publication status	Published - Dec 2022
Externally published	Yes

Bibliographical note

Publisher Copyright:
© 2022, The Author(s).

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Chen, L., Peters, J. E., Prins, B., Persyn, E., Traylor, M., Surendran, P., Karthikeyan, S., Yonova-Doing, E., Di Angelantonio, E., Roberts, D. J., Watkins, N. A., Ouwehand, W. H., Danesh, J., Lewis, C. M., Bronson, P. G., Markus, H. S., Burgess, S., Butterworth, A. S., & Howson, J. M. M. (2022). Systematic Mendelian randomization using the human plasma proteome to discover potential therapeutic targets for stroke. Nature Communications, 13(1), Article 6143. https://doi.org/10.1038/s41467-022-33675-1

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title = "Systematic Mendelian randomization using the human plasma proteome to discover potential therapeutic targets for stroke",

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.",

author = "Lingyan Chen and Peters, {James E.} and Bram Prins and Elodie Persyn and Matthew Traylor and Praveen Surendran and Savita Karthikeyan and Ekaterina Yonova-Doing and {Di Angelantonio}, Emanuele and Roberts, {David J.} and Watkins, {Nicholas A.} and Ouwehand, {Willem H.} and John Danesh and Lewis, {Cathryn M.} and Bronson, {Paola G.} and Markus, {Hugh S.} and Stephen Burgess and Butterworth, {Adam S.} and Howson, {Joanna M.M.}",

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Chen, L, Peters, JE, Prins, B, Persyn, E, Traylor, M, Surendran, P, Karthikeyan, S, Yonova-Doing, E, Di Angelantonio, E, Roberts, DJ, Watkins, NA, Ouwehand, WH, Danesh, J, Lewis, CM, Bronson, PG, Markus, HS, Burgess, S, Butterworth, AS & Howson, JMM 2022, 'Systematic Mendelian randomization using the human plasma proteome to discover potential therapeutic targets for stroke', Nature Communications, vol. 13, no. 1, 6143. https://doi.org/10.1038/s41467-022-33675-1

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AU - Chen, Lingyan

AU - Peters, James E.

AU - Prins, Bram

AU - Persyn, Elodie

AU - Traylor, Matthew

AU - Surendran, Praveen

AU - Karthikeyan, Savita

AU - Yonova-Doing, Ekaterina

AU - Di Angelantonio, Emanuele

AU - Roberts, David J.

AU - Watkins, Nicholas A.

AU - Ouwehand, Willem H.

AU - Danesh, John

AU - Lewis, Cathryn M.

AU - Bronson, Paola G.

AU - Markus, Hugh S.

AU - Burgess, Stephen

AU - Butterworth, Adam S.

AU - Howson, Joanna M.M.

PY - 2022/12

Y1 - 2022/12

N2 - 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.

AB - 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.

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

Abstract

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