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

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作者
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
机构
[1] University of Cambridge,British Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care
[2] Novo Nordisk Research Centre Oxford,Department of Genetics
[3] Imperial College London,Department of Immunology and Inflammation, Faculty of Medicine
[4] King’s College London,Department of Medical and Molecular Genetics
[5] University of Cambridge,Cambridge Baker Systems Genomics Initiative, Department of Public Health and Primary Care
[6] Queen Mary University of London,Clinical Pharmacology, William Harvey Research Institute
[7] University of Cambridge,Rutherford Fund Fellow, Department of Public Health and Primary Care
[8] University of Cambridge,British Heart Foundation Centre of Research Excellence
[9] University of Cambridge,National Institute for Health and Care Research Blood and Transplant Research Unit in Donor Health and Behaviour
[10] Wellcome Genome Campus and University of Cambridge,Health Data Research UK Cambridge
[11] Human Technopole,Health Data Science Research Centre
[12] John Radcliffe Hospital,NHS Blood and Transplant
[13] University of Oxford,Oxford Centre, Level 2
[14] John Radcliffe Hospital,Radcliffe Department of Medicine
[15] Cambridge Biomedical Campus,NHS Blood and Transplant
[16] University of Cambridge,Department of Haematology
[17] Wellcome Sanger Institute,Department of Human Genetics
[18] Wellcome Sanger Institute,Social, Genetic and Developmental Psychiatry Centre
[19] King’s College London,R&D Translational Biology
[20] Biogen,Department of Clinical Neurosciences
[21] Inc.,Medical Research Council Biostatistics Unit, Cambridge Institute of Public Health
[22] University of Cambridge,undefined
[23] University of Cambridge,undefined
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摘要
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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