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Braenne, I.* ; Zeng, L.* ; Willenborg, C.* ; Tragante, V.* ; Kessler, T.* ; Willer, C.J.* ; Laakso, M.* ; Wallentin, L.* ; Franks, P.W.* ; Salomaa, V.* ; Dehghan, A.* ; CARDIoGRAM Consortium (Meitinger, T.) ; Samani, N.J.* ; Asselbergs, F.W.* ; Erdmann, J.* ; Schunkert, H.*

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

PLoS ONE 12:e0182999 (2017)
Publ. Version/Full Text Research data DOI PMC
Open Access Gold
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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 = 1.58x10(-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 x 10(-10) and 2.21 x 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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Publication type Article: Journal article
Document type Scientific Article
Keywords Growth-factor-beta; Tgf-beta; Multiple-sclerosis; Artery-disease; Expression; Cells; Atherosclerosis; Association; Mechanism; Hypertension
Language english
Publication Year 2017
HGF-reported in Year 2017
ISSN (print) / ISBN 1932-6203
Journal PLoS ONE
Quellenangaben Volume: 12, Issue: 8, Pages: , Article Number: e0182999 Supplement: ,
Publisher Public Library of Science (PLoS)
Publishing Place Lawrence, Kan.
Reviewing status Peer reviewed
Institute(s) Institute of Human Genetics (IHG)
POF-Topic(s) 30501 - Systemic Analysis of Genetic and Environmental Factors that Impact Health
Research field(s) Genetics and Epidemiology
PSP Element(s) G-500700-001
PubMed ID 28829817
DOI 10.1371/journal.pone.0182999
WOS ID WOS:000408085100023
Scopus ID 85028551507
Erfassungsdatum 2017-09-08
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