Genomic correlates of glatiramer acetate adverse cardiovascular effects lead to a novel locus mediating coronary risk
Year: 2017
Type: article
Study design: Observational Study
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.
Source: PLoS ONE
Institutions: German Centre for Cardiovascular Research, University of Lübeck, Deutsches Herzzentrum München, Technical University of Munich, University Medical Center Utrecht, University of Michigan, University of Eastern Finland, Kuopio University Hospital, Uppsala University, Lund University, Skåne University Hospital, Finnish Institute for Health and Welfare, Erasmus MC, Helmholtz Munich, Institut für Humangenetik, University of Leicester, Glenfield Hospital, NIHR Leicester Cardiovascular Biomedical Research Unit, Netherlands Heart Institute, University College London
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $1,627
Funders: Bristol-Myers Squibb, Eli Lilly and Company, Pfizer, AstraZeneca, Sanofi, Kaiser Permanente, Itä-Suomen Yliopisto, Helsingin Yliopisto, University of Ottawa, Wellcome Trust, Deutsches Zentrum für Herz-Kreislaufforschung, National Institute for Health and Care Research, Imperial College London, University of Oxford, University of Leeds, European Commission, National Heart and Lung Institute, Deutsche Forschungsgemeinschaft, Fondation Leducq, Institut National de la Santé et de la Recherche Médicale, Bundesministerium für Bildung und Forschung, Università degli Studi di Milano-Bicocca, Erasmus Medisch Centrum, Queen's University, Université de Strasbourg, Johannes Gutenberg-Universität Mainz, Kuopion Yliopistollinen Sairaala, Landspítali Háskólasjúkrahús, Novo Nordisk, Université de Toulouse, Università degli Studi dell'Insubria, Háskóli Íslands, Medizinischen Hochschule Hannover, Technische Universität München, Universität Ulm, Tays, Exzellenzclusters Entzündungsforschung, Medical Research Council, Universitätsmedizin der Johannes Gutenberg-Universität Mainz, National Heart, Lung, and Blood Institute, Institute of Genetics
Awards: Understanding coronary artery disease genes, G1474772629, G2473961061, G3207356259, G393177772, G4267133268, G4760961572, Verbundprojekt sysINFLAME: Netzwerk für Systemmedizin chronisch-entzündlicher Erkrankungen, CP1a, 2, 3, 4 , 5, 7, 8, 9b, 10b, AP, G5702163051, G6388590635, Exploitation of genomic variants affecting coronary artery disease and stroke risk for therapeutic intervention, G6957823285, Verbundprojekt e:AtheroSysMed: Systemmedizin der koronaren Herzkrankheit und des Schlaganfalls, Teilvorhaben Deutsches Herzzentrum München
OpenAlex ID: W2748607562