Systematic Mendelian randomization using the human plasma proteome to discover potential therapeutic targets for stroke
Year: 2022
Type: article
Study design: Observational Study
Abstract: Proteins are the effector molecules of biology and are the target of most drugs. To identify proteins and related pathways that may play a causal role in stroke pathogenesis, we used Mendelian randomisation (MR). We tested potential causal effects of 308 plasma proteins (measured in 4,994 blood donors from the INTERVAL study) on stroke outcomes (derived from the MEGASTROKE GWAS) in a two-sample MR framework and assessed whether these associations could be mediated by cardiovascular risk factors. We extended the analysis to identify whether pharmacological targeting of these proteins might have potential adverse side-effects or beneficial effects for other conditions through Phenome-wide MR (Phe-MR) in UK Biobank. MR showed an association between stroke and genetically predicted plasma levels of TFPI, IL6RA, MMP12, CD40, TMPRSS5 and CD6 (P≤1.62⋅10−4). We identified six risk factors (atrial fibrillation, body mass index, smoking, blood pressure, white matter hyperintensities and type 2 diabetes) that were associated with stroke (P≤0.0071) using MR. The association of TFPI, IL6RA and TMPRSS5 with stroke could be mediated by these risk factors, such as body mass index, white matter hyperintensity and atrial fibrillation. Thirty-six additional proteins were potentially causal for one or more of these risk factors. The Phe-MR suggested that targeting TFPI could have potential beneficial effects on other disorders of arteries and hyperlipidaemia in addition to stroke. Our results highlight novel causal pathways and potential therapeutic targets for stroke.
Source: Nature Communications
Authors: 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
Institutions: University of Cambridge, Imperial College London, King's College London, Queen Mary University of London, William Harvey Research Institute, National Institute for Health and Care Research, Human Technopole, Health Data Research UK, NHS Blood and Transplant, John Radcliffe Hospital, University of Oxford, Wellcome Sanger Institute, Biogen (United States), MRC Biostatistics Unit, British Heart Foundation
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $5,890
Funders: Biogen, NHS Blood and Transplant, South London and Maudsley NHS Foundation Trust, Wellcome Trust, Scottish Government, European Federation of Pharmaceutical Industries and Associations, International Seafood Sustainability Foundation, National Institute for Health and Care Research, British Heart Foundation, Department of Health and Social Care, Royal Society, King's College London, Public Health Agency, Isaac Newton Trust, Chief Scientist Office, Scottish Government Health and Social Care Directorate, NIHR BioResource, NIHR Maudsley Biomedical Research Centre, Medical Research Council, Engineering and Physical Sciences Research Council, Economic and Social Research Council, Health and Social Care Research and Development Division, NIHR Cambridge Biomedical Research Centre, Health Data Research UK
Awards: Genetics and causality: towards more accessible and more reliable Mendelian randomization investigations, G139696651, G1521853241, G1671907826, G1857818866, G1891881142, G1953244154, G2259971274, G2266788633, Large-scale integrative genomic studies of high-dimensional traits in cardiovascular diseases (renewal), G2663141525, G2797452859, G2804450655, G299057155, G3217060148, G3240403866, G3584577881, G370598735, G3715519340, G3986547339, G4194769985, Systematic characterisation of genetically influenced 'omics' phenotypes and disease modules within biological networks, G4504441038, G4584873075, G5117680084, UK Biobank (core renewal), G5484725842, G5512901234, G5546567188, G587296758, G6077662935, G6467398148, G6506225041, G6582518128, G6641991021, G6787924332, G7309080556, Genetics and causality: towards more accessible and more reliable Mendelian randomization investigations, Large-scale integrative studies of risk factors in coronary heart disease: from discovery to application (renewal). (Joint funding with MRC), G762219591, G7631291304, Using genetics to explore the pathophysiology of cerebral small vessel disease. 15, G7826725679, G7939076303, G8131818847, G8346449347, Large-scale integrative studies of risk factors in coronary heart disease: from discovery to application
OpenAlex ID: W4306412215