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

CARDIoGRAM Consortium, CARDIoGRAMplusC4D Consortium, MuTHER Consortium, Wellcome Trust Case Control Consortium

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.

Original languageEnglish
Article numbere0182999
JournalPloS one
Volume12
Issue number8
DOIs
Publication statusPublished - 2017 Aug 1

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Coronary Artery Disease
Genes
acetates
genomics
loci
genes
Single Nucleotide Polymorphism
meta-analysis
Meta-Analysis
coronary artery disease
Glatiramer Acetate
adverse effects
Genome
Chromosomes, Human, Pair 19
drugs
Gene Order
gene interaction
genome
Genome-Wide Association Study
Linkage Disequilibrium

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

Cite this

CARDIoGRAM Consortium, CARDIoGRAMplusC4D Consortium, MuTHER Consortium, & Wellcome Trust Case Control Consortium (2017). Genomic correlates of glatiramer acetate adverse cardiovascular effects lead to a novel locus mediating coronary risk. PloS one, 12(8), [e0182999]. https://doi.org/10.1371/journal.pone.0182999
CARDIoGRAM Consortium ; CARDIoGRAMplusC4D Consortium ; MuTHER Consortium ; Wellcome Trust Case Control Consortium. / Genomic correlates of glatiramer acetate adverse cardiovascular effects lead to a novel locus mediating coronary risk. In: PloS one. 2017 ; Vol. 12, No. 8.
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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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CARDIoGRAM Consortium, CARDIoGRAMplusC4D Consortium, MuTHER Consortium & Wellcome Trust Case Control Consortium 2017, 'Genomic correlates of glatiramer acetate adverse cardiovascular effects lead to a novel locus mediating coronary risk', PloS one, vol. 12, no. 8, e0182999. https://doi.org/10.1371/journal.pone.0182999

Genomic correlates of glatiramer acetate adverse cardiovascular effects lead to a novel locus mediating coronary risk. / CARDIoGRAM Consortium; CARDIoGRAMplusC4D Consortium; MuTHER Consortium; Wellcome Trust Case Control Consortium.

In: PloS one, Vol. 12, No. 8, e0182999, 01.08.2017.

Research output: Contribution to journalArticle

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AU - CARDIoGRAM Consortium

AU - CARDIoGRAMplusC4D Consortium

AU - MuTHER Consortium

AU - Wellcome Trust Case Control Consortium

AU - Brænne, Ingrid

AU - Zeng, Lingyao

AU - Willenborg, Christina

AU - Tragante, Vinicius

AU - Kessler, Thorsten

AU - Willer, Cristen J.

AU - Laakso, Markku

AU - Wallentin, Lars

AU - Franks, Paul W.

AU - Salomaa, Veikko

AU - Dehghan, Abbas

AU - Meitinger, Thomas

AU - Samani, Nilesh J.

AU - Asselbergs, Folkert W.

AU - Erdmann, Jeanette

AU - Schunkert, Heribert

AU - Deloukas, Panos

AU - Kanoni, Stavroula

AU - Farrall, Martin

AU - Assimes, Themistocles L.

AU - Thompson, John R.

AU - Ingelsson, Erik

AU - Saleheen, Danish

AU - Goldstein, Benjamin A.

AU - Absher, Devin

AU - König, Inke R.

AU - Stirrups, Kathleen

AU - Johansson, Åsa

AU - Hall, Alistair S.

AU - Lee, Jong Young

AU - Chambers, John C.

AU - Esko, Tõnu

AU - Folkersen, Lasse

AU - Goel, Anuj

AU - Grundberg, Elin

AU - Havulinna, Aki S.

AU - Ho, Weang K.

AU - Hopewell, Jemma C.

AU - Eriksson, Niclas

AU - Kleber, Marcus E.

AU - Kristiansson, Kati

AU - Lundmark, Per

AU - Lyytikäinen, Leo Pekka

AU - Rafelt, Suzanne

AU - Shun, Dmitry

AU - Strawbridge, Rona J.

AU - Thorleifsson, Gudmar

AU - Tikkanen, Emmi

AU - Van Zuydam, Natalie

AU - Voight, Benjamin F.

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AB - 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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CARDIoGRAM Consortium, CARDIoGRAMplusC4D Consortium, MuTHER Consortium, Wellcome Trust Case Control Consortium. Genomic correlates of glatiramer acetate adverse cardiovascular effects lead to a novel locus mediating coronary risk. PloS one. 2017 Aug 1;12(8). e0182999. https://doi.org/10.1371/journal.pone.0182999