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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
general
Genomic correlates of glatiramer acetate adverse cardiovascular effects lead to a novel locus mediating coronary risk
PLoS ONE, Volume 12, No. 8, Article e0182999, Year 2017
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Description
Glatiramer acetate is used therapeutically in multiple sclerosis but also known for adverse effects including elevated coronary artery disease (CAD) risk. The mechanisms underlying the cardiovascular side effects of the medication are unclear. Here, we made use of the chromosomal variation in the genes that are known to be affected by glatiramer treatment. Focusing on genes and gene products reported by drug-gene interaction database to interact with glatiramer acetate we explored a large meta-analysis on CAD genome-wide association studies aiming firstly, to investigate whether variants in these genes also affect cardiovascular risk and secondly, to identify new CAD risk genes. We traced association signals in a 200-kb region around genomic positions of genes interacting with glatiramer in up to 60 801 CAD cases and 123 504 controls. We validated the identified association in additional 21 934 CAD cases and 76 087 controls. We identified three new CAD risk alleles within the TGFB1 region on chromosome 19 that independently affect CAD risk. The lead SNP rs12459996 was genome-wide significantly associated with CAD in the extended meta-analysis (odds ratio 1.09, p = 1.58×10−12). The other two SNPs at the locus were not in linkage disequilibrium with the lead SNP and by a conditional analysis showed p-values of 4.05 × 10−10 and 2.21 × 10−6. Thus, studying genes reported to interact with glatiramer acetate we identified genetic variants that concordantly with the drug increase the risk of CAD. Of these, TGFB1 displayed signal for association. Indeed, the gene has been associated with CAD previously in both in vivo and in vitro studies. Here we establish genome-wide significant association with CAD in large human samples. © 2017 Brænne et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Authors & Co-Authors
Zeng, Lingyao
Germany, Munich
Technische Universität München
Willenborg, Christina
Germany, Lubeck
Universität zu Lübeck
Tragante, Vinicius
Unknown Affiliation
Kessler, Thorsten
Germany, Munich
Technische Universität München
Willer, Cristen J.
United States, Ann Arbor
University of Michigan School of Public Health
United States, Ann Arbor
University of Michigan, Ann Arbor
Laakso, M. M.
Finland, Kuopio
Itä-suomen Yliopisto
Wallentin, Lars
Sweden, Uppsala
Uppsala Clinical Research Center
Sweden, Uppsala
Uppsala Universitet
Franks, Paul W.
Sweden, Lund
Skånes Universitetssjukhus
United Kingdom, Cambridge
University of Cambridge
Sweden, Umea
Umeå Universitet
United States, Boston
Harvard T.h. Chan School of Public Health
Salomaa, Veikko V.
Finland, Helsinki
Terveyden ja Hyvinvoinnin Laitos
Dehghan, Abbas
Netherlands, Rotterdam
Erasmus Mc
Germany, Lubeck
Universität zu Lübeck
Meitinger, Thomas A.
Germany, Oberschleissheim
Helmholtz Center Munich German Research Center for Environmental Health
Germany, Berlin
Deutsches Zentrum Für Herz-kreislauf-forschung E. V.
Germany, Munich
Technische Universität München
Samani, Nilesh J.
United Kingdom, Leicester
Glenfield Hospital
United Kingdom, Royston
National Institute for Health and Care Research
Asselbergs, Folkert W.
Netherlands, Utrecht
University Medical Center Utrecht
Netherlands, Utrecht
Netherlands Heart Institute
United Kingdom, London
University College London
Erdmann, Jeanette
Germany, Lubeck
Universität zu Lübeck
Germany, Berlin
Deutsches Zentrum Für Herz-kreislauf-forschung E. V.
Germany, Lubeck
University Heart Center Lübeck
Schunkert, Heribert
Germany, Berlin
Deutsches Zentrum Für Herz-kreislauf-forschung E. V.
United Kingdom, Oxford
University of Oxford
United Kingdom, Leeds
University of Leeds, School of Medicine
Germany, Munich
Technische Universität München
Germany, Lubeck
Universität zu Lübeck
Deloukas, Panos
United Kingdom, Hinxton
Wellcome Sanger Institute
Kanoni, Stavroula
United Kingdom, Hinxton
Wellcome Sanger Institute
United States, Boston
Harvard Medical School
Farrall, Martin
United Kingdom, Oxford
University of Oxford
Finland, Kuopio
Itä-suomen Yliopisto
Assimes, Themistocles L.
United States, Stanford
Stanford University School of Medicine
Thompson, John R.
United Kingdom, Leicester
University of Leicester
Ingelsson, Erik
Sweden, Stockholm
Karolinska Institutet
Saleheen, Danish
Pakistan, Karachi
Center for Non-communicable Diseases
United Kingdom, Cambridge
University of Cambridge
United States, Philadelphia
University of Pennsylvania
Absher, Devin Michael
United States, Huntsville
Hudsonalpha Institute for Biotechnology
König, Inke Regina
Germany, Lubeck
Universität zu Lübeck
Stirrups, Kathleen E.
United Kingdom, Hinxton
Wellcome Sanger Institute
United Kingdom, Oxford
University of Oxford
Johansson, Åsa K.
Sweden, Uppsala
Uppsala Universitet
Hall, Alistair Scott
United Kingdom, Leeds
University of Leeds, School of Medicine
Chambers, John Campbell
United Kingdom, London
Imperial College London
Esko, Tönu
Estonia, Tartu
Tartu Ülikool
Folkersen, Lasse
Sweden, Stockholm
Karolinska Institutet
Sweden, Stockholm
Karolinska Universitetssjukhuset
Goel, Anuj
United Kingdom, Oxford
University of Oxford
Grundberg, Elin
United Kingdom, London
King's College London
Havulinna, Aki Samuli
Finland, Helsinki
Terveyden ja Hyvinvoinnin Laitos
Ho, Weang Kee
United States, Philadelphia
University of Pennsylvania
Hopewell, Jemma C.
United Kingdom, Oxford
University of Oxford
Eriksson, Niclas
Sweden, Uppsala
Uppsala Universitet
Kleber, Marcus Edi
Germany, Heidelberg
Universität Heidelberg
Kristiansson, Kati
Finland, Helsinki
Terveyden ja Hyvinvoinnin Laitos
Lundmark, Per E.
Sweden, Uppsala
Uppsala Universitet
Lyytikäinen, Leo Pekka
Finland, Tampere
Fimlab Laboratoriot oy
Finland, Tampere
Tampere University
Thorleifsson, Gudmar
Iceland, Reykjavik
Decode Genetics
Tikkanen, Emmi
Finland, Helsinki
Helsingin Yliopisto
Finland, Helsinki
Terveyden ja Hyvinvoinnin Laitos
van Zuydam, Natalie R.
United Kingdom, Dundee
University of Dundee
Voight, Benjamin F.
United States, Philadelphia
University of Pennsylvania
Waite, Lindsay L.
United States, Huntsville
Hudsonalpha Institute for Biotechnology
Zhang, Weihua
United Kingdom, London
Imperial College London
Altshuler, David M.
United States, Cambridge
Massachusetts Institute of Technology
United States, Boston
Massachusetts General Hospital
United States, Boston
Harvard Medical School
Barroso, Inês E.
United Kingdom, Hinxton
Wellcome Sanger Institute
United Kingdom, Cambridge
Wellcome-mrc Institute of Metabolic Science
Braund, Peter S.
United Kingdom, Leicester
Glenfield Hospital
United Kingdom, Royston
National Institute for Health and Care Research
Cox, David R.
United States, New York
Pfizer Inc.
Dimitriou, Maria E.
Greece, Athens
Harokopio University of Athens
Do, Ron
United States, Cambridge
Massachusetts Institute of Technology
United States, Boston
Massachusetts General Hospital
Doney, Alex S.F.
United Kingdom, Dundee
University of Dundee
El-Mokhtari, Nour Eddine
Unknown Affiliation
Fischer, Krista
Estonia, Tartu
Tartu Ülikool
Fontanillas, Pierre
United States, Cambridge
Massachusetts Institute of Technology
Franco-Cereceda, Anders
Sweden, Stockholm
Karolinska Institutet
Gigante, Bruna
Sweden, Stockholm
Karolinska Institutet
Groop, Leif C.
Sweden, Lund
Skånes Universitetssjukhus
Gustafsson, Stefan
Sweden, Stockholm
Karolinska Institutet
Hager, Jörg
France, Gif-sur-yvette
Commissariat a L'energie Atomique et Aux Energies Alternatives
Hallmans, Goran
Sweden, Umea
Umeå Universitet
Kang, Hyun-min
United States, Ann Arbor
University of Michigan, Ann Arbor
Illig, Thomas
Germany, Hannover
Hannover Medical School
Knowles, Joshua W.
United States, Stanford
Stanford University School of Medicine
Kolovou, Genovefa D.
Greece, Athens
Onassis Cardiac Surgery Centre
Kuusisto, Johanna K.
Finland, Kuopio
Itä-suomen Yliopisto
Langenberg, Claudia C.
United Kingdom, Cambridge
Addenbrooke's Hospital
Langford, Cordelia F.
United Kingdom, Hinxton
Wellcome Sanger Institute
Leander, Karin
Sweden, Stockholm
Karolinska Institutet
Lokki, Marja Liisa L.
Finland, Helsinki
Helsingin Yliopisto
Lundmark, Anders
Sweden, Uppsala
Uppsala Universitet
McCarthy, Mark I.
United Kingdom, Oxford
University of Oxford
United Kingdom, Oxford
Churchill Hospital
Meisinger, Christa
Germany, Oberschleissheim
Helmholtz Center Munich German Research Center for Environmental Health
Melander, Olle
Sweden, Lund
Skånes Universitetssjukhus
Mihailov, Evelin
Estonia, Tartu
Tartu Ülikool
Maouche, Seraya
France, Paris
Sorbonne Université
Morris, Andrew D.
United Kingdom, Dundee
University of Dundee
Müller-Nurasyid, Martina
Germany, Munich
Ludwig-maximilians-universität München
Germany, Oberschleissheim
Helmholtz Center Munich German Research Center for Environmental Health
Nikus, Kjell Christer
Finland, Tampere
University Hospital of Tampere
Peden, John F.
United Kingdom, Oxford
University of Oxford
Rayner, Nigel William
United Kingdom, Oxford
University of Oxford
Rasheed, Asif
United Kingdom, Cambridge
University of Cambridge
Schaefer, Arne S.
Germany, Kiel
Christian-albrechts-universität zu Kiel
Song, Ci
Sweden, Stockholm
Karolinska Institutet
Stewart, Alexandre F.R.
Canada, Ottawa
Institut de Cardiologie de L'université D'ottawa
Tan, Sian Tsung
United Kingdom, London
Imperial College London
Thorgeirsson, Gudmundur
Iceland, Reykjavik
Haskoli Islands
Iceland, Reykjavik
Landspitali - the National University Hospital of Iceland
van der Schoot, C. Ellen
Netherlands, Amsterdam
Stichting Sanquin Bloedvoorziening
Wells, George A.
Canada, Ottawa
Institut de Cardiologie de L'université D'ottawa
Wild, Philipp S.
Germany, Mainz
Johannes Gutenberg-universität Mainz
Yang, Tsunpo
United Kingdom, Hinxton
Wellcome Sanger Institute
Amouyel, Philippe
France, Lille
Institut Pasteur de Lille
Arveiler, Dominique
France, Strasbourg
Université de Strasbourg
Boehnke, Michael L.
United States, Ann Arbor
University of Michigan, Ann Arbor
Boerwinkle, Eric A.
United States, Houston
University of Texas Health Science Center at Houston
Brambilla, Paolo
Italy, Milan
Università Degli Studi Di Milano-bicocca
Cambien, François A.
France, Paris
Sorbonne Université
Cupples, Laura Adrienne
United States, Boston
School of Public Health
United States, Framingham
Framingham Heart Study
Dé Fairé, Ulf H.
Sweden, Stockholm
Karolinska Institutet
Diemert, Patrick
Germany, Hamburg
Universitäre Herz- Und Gefäßzentrum Uke Hamburg Gmbh
Epstein, Stephen E.
United States, Washington, D.c.
Washington Hospital Center
Evans, Alun E.
United Kingdom, Belfast
Queen's University Belfast
Ferrario, Marco Mario
Italy, Varese
Università Degli Studi Dell'insubria
Ferrières, Jean
France, Toulouse
Hôpital Rangueil
Gauguier, Dominique
United Kingdom, Oxford
University of Oxford
France, Paris
Inserm
Goodall, Alison H.
United Kingdom, Leicester
Glenfield Hospital
United Kingdom, Royston
National Institute for Health and Care Research
Gudnason, V. G.
Iceland, Reykjavik
Haskoli Islands
Iceland, Kopavogur
Icelandic Heart Association
Hazen, Stanley L.
United States, Cleveland
Cleveland Clinic Foundation
Hólm, Hilma
Iceland, Reykjavik
Decode Genetics
Iribarren, Carlos
United States, Oakland
Kaiser Permanente
Jang, Yangsoo
South Korea, Seoul
Yonsei University
Kähönen, Mika A.P.
Finland, Tampere
Tampere University
Kee, Frank
United Kingdom, Belfast
Queen's University Belfast
Kim, Hyosoo
South Korea, Seoul
Seoul National University Hospital
Klopp, Norman
Germany, Hannover
Hannover Medical School
Koenig, Wolfgang F.
Germany, Ulm
Universitätsklinikum Ulm
Kratzer, Wolfgang
Finland, Tampere
University Hospital of Tampere
Kuulasmaa, Kari A.
Finland, Helsinki
Terveyden ja Hyvinvoinnin Laitos
Laaksonen, Reijo M.H.
Finland, Tampere
University Hospital of Tampere
Lind, Lars L.
Sweden, Uppsala
Uppsala Universitet
Ouwehand, Willem Hendrik
United Kingdom, Hinxton
Wellcome Sanger Institute
United Kingdom, Cambridge
University of Cambridge
United Kingdom, Bristol
Nhs Blood and Transplant
Park, Jeong-euy
South Korea, Seoul
Samsung Medical Center, Sungkyunkwan University
Pedersen, Nancy Lee
Sweden, Stockholm
Karolinska Institutet
Peters, Annette Michael
Germany, Oberschleissheim
Helmholtz Center Munich German Research Center for Environmental Health
Assimes, Themistocles L.
United States, Stanford
Stanford University School of Medicine
Rader, Daniel J.
United States, Philadelphia
University of Pennsylvania Perelman School of Medicine
Schadt, Eric E.
United States, New York
Icahn School of Medicine at Mount Sinai
Shah, Svati H.
United States, Durham
Duke University Medical Center
Sinisalo, Juha P.
Finland, Helsinki
Helsinki University Hospital
Stefánsson, Kari
Iceland, Reykjavik
Decode Genetics
Iceland, Reykjavik
Haskoli Islands
Trégouët, David Alexandre
France, Paris
Sorbonne Université
Virtamo, Jarmo R.K.
Finland, Helsinki
Terveyden ja Hyvinvoinnin Laitos
Wareham, Nicholas J.
United Kingdom, Cambridge
Addenbrooke's Hospital
Nieminen, Markku Sakari
Finland, Helsinki
Helsinki University Hospital
Sandhu, Manjinder Singh
United Kingdom, Hinxton
Wellcome Sanger Institute
United Kingdom, Cambridge
Addenbrooke's Hospital
Pastinen, Tomi M.
Canada, Montreal
Université Mcgill
Syvänen, Ann Christine
Sweden, Uppsala
Uppsala Universitet
Hovingh, Gerard Kees
Unknown Affiliation
Dedoussis, George V.Z.
Greece, Athens
Harokopio University of Athens
Lehtimäki, Terho J.
Finland, Tampere
Fimlab Laboratoriot oy
Finland, Tampere
Tampere University
Metspalu, Andres H.
Estonia, Tartu
Tartu Ülikool
Zalloua, Pierre A.
Lebanon, Beirut
Lebanese American University
Siegbahn, Agneta
Sweden, Uppsala
Uppsala Universitet
Schreiber, Stefan W.
Germany, Kiel
Christian-albrechts-universität zu Kiel
Ripatti, Samuli O.
United Kingdom, Hinxton
Wellcome Sanger Institute
Finland, Helsinki
Terveyden ja Hyvinvoinnin Laitos
Blankenberg, Stefan S.
Germany, Hamburg
Universitäre Herz- Und Gefäßzentrum Uke Hamburg Gmbh
Perola, Markus
Finland, Helsinki
Terveyden ja Hyvinvoinnin Laitos
Clarke, Robert Joseph
United Kingdom, Oxford
University of Oxford
O'Donnell, Christopher J.
Netherlands, Rotterdam
Erasmus Mc
Reilly, Muredach P.
United States, Philadelphia
University of Pennsylvania
Mar̈z, Winfried
Germany, Heidelberg
Universität Heidelberg
Germany, Munich
Synlab International Gmbh
Collins, Rory
United Kingdom, Oxford
University of Oxford
Kathiresan, Sekar
United States, Cambridge
Massachusetts Institute of Technology
United States, Boston
Massachusetts General Hospital
United States, Cambridge
Broad Institute
Hamsten, Anders
Sweden, Stockholm
Karolinska Institutet
Sweden, Stockholm
Karolinska Universitetssjukhuset
Kooner, Jaspal Singh
Unknown Affiliation
Thorsteinsdóttir, Unnur Arna
Iceland, Reykjavik
Decode Genetics
Iceland, Reykjavik
Haskoli Islands
Danesh, John N.
United Kingdom, Cambridge
University of Cambridge
Palmer, Colin Neil Alexander
United Kingdom, Dundee
University of Dundee
Roberts, Robert
Canada, Ottawa
Institut de Cardiologie de L'université D'ottawa
Watkins, Hugh C.
United Kingdom, Oxford
University of Oxford
Hengstenberg, Christian
Germany, Lubeck
Universität zu Lübeck
Germany, Regensburg
Universität Regensburg
McPherson, Ruth
Canada, Ottawa
Institut de Cardiologie de L'université D'ottawa
Ziegler, Andreas E.
Germany, Lubeck
Universität zu Lübeck
Statistics
Citations: 4
Authors: 164
Affiliations: 94
Identifiers
Doi:
10.1371/journal.pone.0182999
ISSN:
19326203
Research Areas
Genetics And Genomics
Health System And Policy
Noncommunicable Diseases
Study Design
Case-Control Study
Study Approach
Systematic review