TY - JOUR
T1 - Druggable proteins influencing cardiac structure and function
T2 - Implications for heart failure therapies and cancer cardiotoxicity
AU - Schmidt, Amand F.
AU - Bourfiss, Mimount
AU - Alasiri, Abdulrahman
AU - Puyol-Anton, Esther
AU - Chopade, Sandesh
AU - van Vugt, Marion
AU - van der Laan, Sander W.
AU - Gross, Christian
AU - Clarkson, Chris
AU - Henry, Albert
AU - Lumbers, Tom R.
AU - van der Harst, Pim
AU - Franceschini, Nora
AU - Bis, Joshua C.
AU - Velthuis, Birgitta K.
AU - te Riele, Anneline S. J. M.
AU - Hingorani, Aroon D.
AU - Ruijsink, Bram
AU - Asselbergs, Folkert W.
AU - van Setten, Jessica
AU - Finan, Chris
N1 - Funding Information:
This research has been conducted using the UK Biobank Resource under application numbers 12113 and 24711. We are grateful to the UK Biobank participants. UK Biobank was established by the Wellcome Trust medical charity, Medical Research Council, Department of Health, Scottish Government, and the Northwest Regional Development Agency. It has also had funding from the Welsh Assembly Government and the British Heart Foundation. A.F.S. is supported by BHF grant PG/18/5033837, PG/22/10989, and the UCL BHF Research Accelerator AA/18/6/34223. M.B. is supported by the Alexandre Suerman Stipend of the UMC Utrecht (2017). C.F. and A.F.S. received additional support from the National Institute for Health Research University College London Hospitals Biomedical Research Centre. A.D.H. is an NIHR Senior Investigator. F.W.A. and A.F.S. received grant funding from the EU Horizon scheme (AI4HF 101080430 and DataTools4Heart 101057849) and the Dutch Research Council (MyDigiTwin 628.011.213). J.v.S. and M.v.V. are supported by Dutch Heart Foundation grant 2019 T045. ATR is supported by the CardioVascular Research Initiative of the Netherlands Heart Foundation (CVON 2015-12 eDETECT and 2012-10 PREDICT) and Dutch Heart Foundation grant number 2015T058. S.W.v.d.L. is funded through grants from the Netherlands CardioVascular Research Initiative of the Netherlands Heart Foundation (CVON 2011/B019 and CVON 2017-20) and is additionally supported by the ERA-CVD program (grant number 01KL1802), the EU H2020 TO_AITION (grant number 848146), and the Leducq Fondation “PlaqOmics.” A.A. is supported by King Abdullah International Medical Research Center (KAIMRC). This work was supported by grant R01 LM010098 from the National Institutes of Health (USA), the EU/EFPIA Innovative Medicines Initiative 2 Joint Undertaking BigData@Heart (grant number 116074), the Horizon EiC Pathfinder project DMC-next (grant number 101115416), as well as by the UKRI/NIHR Multimorbidity fund Mechanism and Therapeutics Research Collaborative MR/V033867/1 and the Rosetrees Trust. Infrastructure for the CHARGE Consortium is supported in part by National Heart, Lung, and Blood Institute grant R01HL105756.
Funding Information:
Acknowledgments: This research has been conducted using the UK Biobank Resource under applicationnumbers12113and24711.W earegra teful totheUKBiobankparticipants.UK BiobankwasestablishedbytheW ellcome Trustmedicalcharity,MedicalResearchCouncil, DepartmentofHealth,ScottishGovernment,andtheNorthwestRegionalDevelopment Agency.IthasalsohadfundingfromtheW elsh AssemblyGovernmentandtheBritishHeart Foundation.Funding:A.F .S. issupportedbyBHFgrantPG/18/5033837,PG/22/10989,andthe UCLBHFResearchAcceleratorAA/18/6/34223.M.B.issupportedbytheAlexandreSuerman StipendoftheUMCUtrecht(2017).C.F .andA.F .S. receivedadditionalsupportfromtheNational InstituteforHealthResearchUniversityCollegeLondonHospitalsBiomedicalResearchCentre. A.D.H. is an NIHR Senior Investigator. F .W .A. and A.F .S. received grant funding from the EU Horizonscheme(AI4HF101080430andDataTools4Heart101057849)andtheDutchResearch Council(MyDigiTwin628.011.213).J.v.S.andM.v.V .aresupportedbyDutchHeartFoundation grant2019T045.A TR issupportedbytheCardioVascularResearchInitiativeoftheNetherlands HeartFoundation(CVON2015-12eDETECTand2012-10PREDICT)andDutchHeartFoundation grantnumber2015T058.S.W .v.d.L. isfundedthroughgrantsfromtheNetherlands CardioVascularResearchInitiativeoftheNetherlandsHeartFoundation(CVON2011/B019and CVON2017-20)andisadditionallysupportedbytheERA-CVDprogr am (grantnumber 01KL1802),theEUH2020TO_AITION(grantnumber848146),andtheLeducqFondation “PlaqOmics. ”A.A.issupportedbyKingAbdullahInternationalMedicalResearchCenter (KAIMRC).ThisworkwassupportedbygrantR01LM010098fromtheNationalInstitutesof Health(USA),theEU/EFPIAInnovativeMedicinesInitiativ e2JointUndertakingBigData@Heart (grantnumber116074),theHorizonEiCPa thfinder projectDMC-next(grantnumber 101115416),aswellasbytheUKRI/NIHRMultimorbidityfundMechanismandTherapeutics ResearchCollaborativeMR/V033867/1andtheRosetreesTrust.InfrastructurefortheCHARGE ConsortiumissupportedinpartbyNationalHeart,Lung,andBloodInstitutegrant R01HL105756.Authorcontributions:A.F .S., M.B.,F .W .A., J.v.S.,andC.F .contributedtotheidea anddesignofthestudy.A.F .S., M.B.,A.A.,andC.F .performedtheanalyses.A.F .S., J.v.S.,M.B.,and C.F .draftedthemanuscript.Allauthorsprovidedcriticalinputontheanalysesandthedrafted manuscript.Competinginterests:A.F .S. andF .W .A. havereceivedServierfundingforunrelated work. S.W .v.d.L. has received Roche funding for unrelated work. C.G. receives a salary from SkylineDxBV;SkylineDxBVhadnocontributiontothecontentofthispublication.Theauthors declarenoothercompetinginterests.Dataandmaterialsavailability:ThesourceGW AS CMR data,aswellasthevariantleveldatausedfortheMendelianrandomizationanalyses,havebeen deposited on figshare: https://doi.org/10.5522/04/21603651.v3. The same figshare repository alsocontainsthepythonmodulegwas_normusedtoformat-normalizetheaggregateGW AS datalistednext.W eleveragedpQTLdatafromtheresources,whichcanbeaccessedfrom https://ega-archive.org/studies/EGAS00001002555(interval),https://zenodo.org/record/
Publisher Copyright:
Copyright © 2023 Authors, some rights reserved.
PY - 2023/4/28
Y1 - 2023/4/28
N2 - Dysfunction of either the right or left ventricle can lead to heart failure (HF) and subsequent morbidity and mortality. We performed a genome-wide association study (GWAS) of 16 cardiac magnetic resonance (CMR) imaging measurements of biventricular function and structure. Cis-Mendelian randomization (MR) was used to identify plasma proteins associating with CMR traits as well as with any of the following cardiac outcomes: HF, non-ischemic cardiomyopathy, dilated cardiomyopathy (DCM), atrial fibrillation, or coronary heart disease. In total, 33 plasma proteins were prioritized, including repurposing candidates for DCM and/or HF: IL18R (providing indirect evidence for IL18), I17RA, GPC5, LAMC2, PA2GA, CD33, and SLAF7. In addition, 13 of the 25 druggable proteins (52%; 95% confidence interval, 0.31 to 0.72) could be mapped to compounds with known oncological indications or side effects. These findings provide leads to facilitate drug development for cardiac disease and suggest that cardiotoxicities of several cancer treatments might represent mechanism-based adverse effects.
AB - Dysfunction of either the right or left ventricle can lead to heart failure (HF) and subsequent morbidity and mortality. We performed a genome-wide association study (GWAS) of 16 cardiac magnetic resonance (CMR) imaging measurements of biventricular function and structure. Cis-Mendelian randomization (MR) was used to identify plasma proteins associating with CMR traits as well as with any of the following cardiac outcomes: HF, non-ischemic cardiomyopathy, dilated cardiomyopathy (DCM), atrial fibrillation, or coronary heart disease. In total, 33 plasma proteins were prioritized, including repurposing candidates for DCM and/or HF: IL18R (providing indirect evidence for IL18), I17RA, GPC5, LAMC2, PA2GA, CD33, and SLAF7. In addition, 13 of the 25 druggable proteins (52%; 95% confidence interval, 0.31 to 0.72) could be mapped to compounds with known oncological indications or side effects. These findings provide leads to facilitate drug development for cardiac disease and suggest that cardiotoxicities of several cancer treatments might represent mechanism-based adverse effects.
KW - Atrial Fibrillation
KW - Cardiomyopathy, Dilated
KW - Cardiotoxicity
KW - Genome-Wide Association Study
KW - Glypicans
KW - Heart Failure
KW - Humans
KW - Neoplasms
UR - https://www.scopus.com/pages/publications/85158033415
U2 - 10.1126/sciadv.add4984
DO - 10.1126/sciadv.add4984
M3 - Article
C2 - 37126556
SN - 2375-2548
VL - 9
SP - eadd4984
JO - Science advances
JF - Science advances
IS - 17
M1 - eadd4984
ER -
SDG 3 Good Health and Well-being