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

Research output: Contribution to journalArticle

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.

Details

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
  • Heribert Schunkert
  • CARDIoGRAM Consortium
Organisations
External organisations
  • Finnish National Institute for Health and Welfare
  • University of Lübeck
  • Technical University of Munich
  • Utrecht University
  • University of Michigan
  • University of Eastern Finland
  • Uppsala University
  • Erasmus University Medical Center
  • University of Leicester
  • Glenfield Hospital
  • University College London
  • German Centre for Cardiovascular Research
  • University Heart Center Lübeck
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Medical Genetics

Keywords

  • Journal Article
Original languageEnglish
Pages (from-to)e0182999
JournalPLoS ONE
Volume12
Issue number8
Publication statusPublished - 2017
Publication categoryResearch
Peer-reviewedYes