Advanced

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

Brænne, Ingrid; Zeng, Lingyao; Willenborg, Christina; Tragante, Vinicius; Kessler, Thorsten; Willer, Cristen J; Laakso, Markku; Wallentin, Lars LU ; Franks, Paul W LU and Salomaa, Veikko, et al. (2017) In PLoS ONE 12(8). p.0182999-0182999
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... (More)

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.

(Less)
Please use this url to cite or link to this publication:
author
, et al. (More)
(Less)
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Journal Article
in
PLoS ONE
volume
12
issue
8
pages
0182999 - 0182999
publisher
Public Library of Science
external identifiers
  • scopus:85028551507
  • wos:000408085100023
ISSN
1932-6203
DOI
10.1371/journal.pone.0182999
language
English
LU publication?
yes
id
77551bd2-7a6a-4ec2-bdcb-bfc86fae5ad0
date added to LUP
2017-10-04 15:55:37
date last changed
2018-03-27 13:39:04
@article{77551bd2-7a6a-4ec2-bdcb-bfc86fae5ad0,
  abstract     = {<p>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.</p>},
  author       = {Brænne, Ingrid and Zeng, Lingyao and Willenborg, Christina and Tragante, Vinicius and Kessler, Thorsten and Willer, Cristen J and Laakso, Markku and Wallentin, Lars and Franks, Paul W and Salomaa, Veikko and Dehghan, Abbas and Meitinger, Thomas and Samani, Nilesh J. and Asselbergs, Folkert W and Erdmann, Jeanette and Schunkert, Heribert and , },
  issn         = {1932-6203},
  keyword      = {Journal Article},
  language     = {eng},
  number       = {8},
  pages        = {0182999--0182999},
  publisher    = {Public Library of Science},
  series       = {PLoS ONE},
  title        = {Genomic correlates of glatiramer acetate adverse cardiovascular effects lead to a novel locus mediating coronary risk},
  url          = {http://dx.doi.org/10.1371/journal.pone.0182999},
  volume       = {12},
  year         = {2017},
}