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- Title
Systematic Mendelian randomization using the human plasma proteome to discover potential therapeutic targets for stroke.
- Authors
Chen, Lingyan; Peters, James E.; Prins, Bram; Persyn, Elodie; Traylor, Matthew; Surendran, Praveen; Karthikeyan, Savita; Yonova-Doing, Ekaterina; Di Angelantonio, Emanuele; Roberts, David J.; Watkins, Nicholas A.; Ouwehand, Willem H.; Danesh, John; Lewis, Cathryn M.; Bronson, Paola G.; Markus, Hugh S.; Burgess, Stephen; Butterworth, Adam S.; Howson, Joanna M. M.
- 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. Mendelian randomization can be used to mimic the effects of protein-targeting drugs in a population of individuals. Here, the authors have identified potential causal proteins for stroke in a two-sample Mendelian randomization framework, providing potential stroke therapeutic targets.
- Subjects
DRUG target; DISEASE risk factors; BLOOD proteins; BODY mass index; TYPE 2 diabetes; ATRIAL fibrillation
- Publication
Nature Communications, 2022, Vol 13, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-022-33675-1