Journal Article

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

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

2022

Overview

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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 45 / 45/43 / 631/208/2489/144 / 692/499 / 692/699/75 / Atrial Fibrillation - genetics / Blood plasma / Blood pressure / Blood Proteins - genetics / Body mass index / Body size / Cardiac arrhythmia / CD40 antigen / CD6 antigen / Conditional probability / Diabetes mellitus (non-insulin dependent) / Diabetes Mellitus, Type 2 - genetics / Drug delivery / Drug development / Fibrillation / Genetic Predisposition to Disease / Genome-Wide Association Study / Health risks / Humanities and Social Sciences / Humans / Interleukin 6 / Mendelian Randomization Analysis / multidisciplinary / Plasma levels / Plasma proteins / Polymorphism, Single Nucleotide / Proteins / Proteome - genetics / Proteomes / Randomization / Risk analysis / Risk Factors / Science / Science (multidisciplinary) / Stroke / Stroke - genetics / Substantia alba / Therapeutic applications / Therapeutic targets