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Genomic correlates of glatiramer acetate adverse cardiovascular effects lead to a novel locus mediating coronary risk

Genomic correlates of glatiramer acetate adverse cardiovascular effects lead to a novel locus mediating coronary risk

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Authors

  • Ingrid Brænne
  • Lingyao Zeng
  • Christina Willenborg
  • Vinicius Tragante
  • Thorsten Kessler
  • Cristen J. Willer
  • Markku Laakso
  • Lars Wallentin
  • Paul W. Franks
  • Veikko Salomaa
  • Abbas Dehghan
  • Thomas Meitinger
  • Nilesh J. Samani
  • Folkert W. Asselbergs
  • Jeanette Erdmann (Lead / Corresponding author)
  • Heribert Schunkert
  • Panos Deloukas
  • Stavroula Kanoni
  • Christina Willenborg
  • Martin Farrall
  • Themistocles L. Assimes
  • John R. Thompson
  • Erik Ingelsson
  • Danish Saleheen
  • Jeanette Erdmann
  • Benjamin A. Goldstein
  • Kathleen Stirrups
  • Inke R. König
  • Jean-Baptiste Cazier
  • Åsa Johansson
  • Alistair S. Hall
  • Jong-Young Lee
  • Cristen J. Willer
  • John C. Chambers
  • Tõnu Esko
  • Lasse Folkersen
  • Anuj Goel
  • Elin Grundberg
  • Aki S. Havulinna
  • Weang Kee Ho
  • Jemma C. Hopewell
  • Niclas Eriksson
  • Marcus E. Kleber
  • Kati Kristiansson
  • Per Lundmark
  • Leo-Pekka Lyytikäinen
  • Suzanne Rafelt
  • Dmitry Shun
  • Rona J. Strawbridge
  • Gudmar Thorleifsson
  • Emmi Tikkanen
  • Natalie Van Zuydam
  • Benjamin F. Voight
  • Lindsay L. Waite
  • Weihua Zhang
  • Andreas Zieg
  • Devin M. Absher
  • David Altshuler
  • Anthony J. Balmforth
  • Inês Barroso
  • Peter S. Braund
  • Christof Burgdorf
  • Simone Claudi-Boehm
  • David N. Cox
  • Maria Dimitriou
  • Ron Do
  • Alex S.F. Doney
  • Nour Eddine El-Mokhtari
  • Per Eriksson
  • Krista Fischer
  • Pierre Fontanillas
  • Anders Franco-Cereceda
  • Bruna Gigante
  • Leif C. Groop
  • Stefan Gustafsson
  • Jörg Hager
  • Göran Hallmans
  • Bok-Ghee Han
  • Sarah Ehunt
  • Hyun Min Kang
  • Thomas Illig
  • Thorsten Kessler
  • Joshua W. Knowles
  • Genovefa Kolovou
  • Johanna Kuusisto
  • Claudia Langenberg
  • Cordelia F. Langford
  • Karin Leander
  • Marja-Liisa Lokki
  • Anders Lundmark
  • Mark I. McCarthy
  • Christa Meisinger
  • Olle Melander
  • Evelin Mihailov
  • Seraya Maouche
  • Andrew D. Morris
  • Martina Müller-Nurasyid
  • Kjell Nikus
  • John F. Peden
  • N. William Rayner
  • Asif Rasheed
  • Silke Rosinger
  • Diana Rubin
  • Moritz P. Rumpf
  • Arne Schäfer
  • Mohan Sivananthan
  • Ci Song
  • Alexandre F. R. Stewart
  • Sian-Tsung Tan
  • Gudmundur Thorgeirsson
  • C. Ellen van der Schoot
  • Peter J. Wagner
  • George A. Wells
  • Philipp S. Wild
  • Tsun-Po Yang
  • Philippe Amouyel
  • Dominique Arveiler
  • Hanneke Basart
  • Michael Boehnke
  • Eric Boerwinkle
  • Paolo Brambilla
  • Francois Cambien
  • L. Adrienne Cupples
  • Ulf de Faire
  • Abbas Dehghan
  • Patrick Diemert
  • Stephen E. Epstein
  • Alun Evans
  • Marco M. Ferrario
  • Jean Ferrières
  • Dominique Gauguier
  • Alan S. Go
  • Alison H. Goodall
  • Villi Gudnason
  • Stanley L. Hazen
  • Hilma Holm
  • Carlos Iribarren
  • Yangsoo Jang
  • Mika Kähönen
  • Frank Kee
  • Hyo Soo Kim
  • Norman Klopp
  • Wolfgang Koenig
  • Wolfgang Kratzer
  • Kari Kuulasmaa
  • Markku Laakso
  • Reijo Laaksonen
  • Ji-Young Lee
  • Lars Lind
  • Willem H. Ouwehand
  • Sarah Parish
  • Jeong E. Park
  • Nancy L. Pedersen
  • Annette Peters
  • Thomas Quertermous
  • Daniel J. Rader
  • Veikko Salomaa
  • Eric E. Schadt
  • Svati H. Shah
  • Juha Sinisalo
  • Klaus Stark
  • Kari Stefansson
  • David-Alexandre Trégouët
  • Jarmo Virtamo
  • Lars Wallentin
  • Nicholas J. Wareham
  • Martina E. Zimmermann
  • Markku S. Nieminen
  • Christian Hengsten
  • Manjinder S. Sandhu
  • Tomi Pastinen
  • Ann-Christine Syvänen
  • G. Kees Hovingh
  • George Dedoussis
  • Paul W. Franks
  • Terho Lehtimäki
  • Andres Metspalu
  • Pierre A. Zalloua
  • Agneta Siegbahn
  • Stefan Schreiber
  • Samuli Ripatti
  • Stefan S. Blankenberg
  • Markus Perola
  • Robert Clarke
  • Bernhard Oboehm
  • Christopher O’Donnell
  • Muredach P. Reilly
  • Winfried März
  • Rory Collins
  • Sekar Kathiresan
  • Anders Hamsten
  • Jaspal S. Kooner
  • Unnur Thorsteinsdottir
  • John Danesh
  • Colin N.A. Palmer
  • Robert Roberts
  • Hugh Watkins
  • Heribert Schunkert
  • Nilesh J. Samani
  • Themistocles L. Assimes
  • Eric Boerwinkle
  • Jeanette Erdmann
  • Alistair S. Hall
  • Christian Hengstenberg
  • Sekar Kathiresan
  • Inke R. König
  • Reijo Laaksonen
  • Ruth McPherson
  • Muredach P. Reilly
  • Nilesh J. Samani
  • Heribert Schunkert
  • John R. Thompson
  • Unnur Thorsteinsdottir
  • Andreas Ziegler
  • CARDIoGRAM Consortium
  • CARDIoGRAMplusC4D Consortium
  • MuTHER Consortium
  • Wellcome Trust Case Control Consortium

Research units

Info

Original languageEnglish
Article numbere0182999
Pages (from-to)1-19
Number of pages19
JournalPLoS ONE
Volume12
Issue number8
DOIs
StatePublished - 22 Aug 2017

Abstract

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.

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    Copyright: © 2017 Brænne et al. This is an open
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