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

doi: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

Department of Internal Medicine

Research output: Contribution to journal › Article › peer-review

3 Citations (Scopus)

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 language	English
Article number	e0182999
Journal	PloS one
Volume	12
Issue number	8
DOIs	https://doi.org/10.1371/journal.pone.0182999
Publication status	Published - 2017 Aug 1

Bibliographical note

Funding Information:
Funding:Thisworkwassupportedbygrantsfrom theFondationLeducq(CADgenomics: UnderstandingCADGenes,12CVD02),theGerman FederalMinistryofEducationandResearch (BMBF)withintheframeworkofthee:Med researchandfundingconcept(e:AtheroSysMed, grant01ZX1313A-2014andSysInflame,grant

Funding Information:
ThisworkwassupportedbygrantsfromtheFondationLeducq(CADgenomics:Understanding CADGenes,12CVD02),theGermanFederalMinistryofEducationandResearch(BMBF)within the framework of the e:Med research and funding concept (e:A ther oS ysM ed, grant 01ZX1313A-2014 and S ysI nflame, grant 01ZX1306A), and the European Union Seventh Framework Pro-grammeFP7/2007-2013undergrantagreementnoHEALTH-F2-2013-601456(CVgenes-a t-t ar-get).FurthergrantswerereceivedfromtheDFGaspartoftheSonderforschungsbereich CRC 1123(B2).T.K.wassupportedbyaDZHKRotationGrant.I.B.wassupportedbytheDeutsche Forschungsgemeinschaft(DFG)clusterofexcellence‘InflammationatInterfaces’.F.W.A.issup-portedbyaDekkerscholarship-JuniorStaffMember2014T001-NetherlandsHeartFoundation andUCLHospitalsNIHRBiomedicalResearchCentre.

Publisher Copyright:
© 2017 Brænne et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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10.1371/journal.pone.0182999

Cite this

@article{867d7dd054e24a25a4632e376917a890,

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

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.",

author = "{CARDIoGRAM Consortium} and {CARDIoGRAMplusC4D Consortium} and {MuTHER Consortium} and {Wellcome Trust Case Control Consortium} and Ingrid Br{\ae}nne and Lingyao Zeng and Christina Willenborg and Vinicius Tragante and Thorsten Kessler and Willer, {Cristen J.} and Markku Laakso and Lars Wallentin and Franks, {Paul W.} and Veikko Salomaa and Abbas Dehghan and Thomas Meitinger and Samani, {Nilesh J.} and Asselbergs, {Folkert W.} and Jeanette Erdmann and Heribert Schunkert and Panos Deloukas and Stavroula Kanoni and Martin Farrall and Assimes, {Themistocles L.} and Thompson, {John R.} and Erik Ingelsson and Danish Saleheen and Goldstein, {Benjamin A.} and Devin Absher and K{\"o}nig, {Inke R.} and Kathleen Stirrups and {\AA}sa Johansson and Hall, {Alistair S.} and Lee, {Jong Young} and Chambers, {John C.} and T{\~o}nu Esko and Lasse Folkersen and Anuj Goel and Elin Grundberg and Havulinna, {Aki S.} and Ho, {Weang K.} and Hopewell, {Jemma C.} and Niclas Eriksson and Kleber, {Marcus E.} and Kati Kristiansson and Per Lundmark and Lyytik{\"a}inen, {Leo Pekka} and Suzanne Rafelt and Dmitry Shun and Strawbridge, {Rona J.} and Gudmar Thorleifsson and Emmi Tikkanen and {Van Zuydam}, Natalie and Yangsoo Jang",

note = "Funding Information: Funding:Thisworkwassupportedbygrantsfrom theFondationLeducq(CADgenomics: UnderstandingCADGenes,12CVD02),theGerman FederalMinistryofEducationandResearch (BMBF)withintheframeworkofthee:Med researchandfundingconcept(e:AtheroSysMed, grant01ZX1313A-2014andSysInflame,grant Funding Information: ThisworkwassupportedbygrantsfromtheFondationLeducq(CADgenomics:Understanding CADGenes,12CVD02),theGermanFederalMinistryofEducationandResearch(BMBF)within the framework of the e:Med research and funding concept (e:A ther oS ysM ed, grant 01ZX1313A-2014 and S ysI nflame, grant 01ZX1306A), and the European Union Seventh Framework Pro-grammeFP7/2007-2013undergrantagreementnoHEALTH-F2-2013-601456(CVgenes-a t-t ar-get).FurthergrantswerereceivedfromtheDFGaspartoftheSonderforschungsbereich CRC 1123(B2).T.K.wassupportedbyaDZHKRotationGrant.I.B.wassupportedbytheDeutsche Forschungsgemeinschaft(DFG)clusterofexcellence{\textquoteleft}InflammationatInterfaces{\textquoteright}.F.W.A.issup-portedbyaDekkerscholarship-JuniorStaffMember2014T001-NetherlandsHeartFoundation andUCLHospitalsNIHRBiomedicalResearchCentre. Publisher Copyright: {\textcopyright} 2017 Br{\ae}nne et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.",

year = "2017",

month = aug,

day = "1",

doi = "10.1371/journal.pone.0182999",

language = "English",

volume = "12",

journal = "PLoS One",

issn = "1932-6203",

publisher = "Public Library of Science",

number = "8",

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TY - JOUR

T1 - Genomic correlates of glatiramer acetate adverse cardiovascular effects lead to a novel locus mediating coronary risk

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 - Jang, Yangsoo

N1 - Funding Information: Funding:Thisworkwassupportedbygrantsfrom theFondationLeducq(CADgenomics: UnderstandingCADGenes,12CVD02),theGerman FederalMinistryofEducationandResearch (BMBF)withintheframeworkofthee:Med researchandfundingconcept(e:AtheroSysMed, grant01ZX1313A-2014andSysInflame,grant Funding Information: ThisworkwassupportedbygrantsfromtheFondationLeducq(CADgenomics:Understanding CADGenes,12CVD02),theGermanFederalMinistryofEducationandResearch(BMBF)within the framework of the e:Med research and funding concept (e:A ther oS ysM ed, grant 01ZX1313A-2014 and S ysI nflame, grant 01ZX1306A), and the European Union Seventh Framework Pro-grammeFP7/2007-2013undergrantagreementnoHEALTH-F2-2013-601456(CVgenes-a t-t ar-get).FurthergrantswerereceivedfromtheDFGaspartoftheSonderforschungsbereich CRC 1123(B2).T.K.wassupportedbyaDZHKRotationGrant.I.B.wassupportedbytheDeutsche Forschungsgemeinschaft(DFG)clusterofexcellence‘InflammationatInterfaces’.F.W.A.issup-portedbyaDekkerscholarship-JuniorStaffMember2014T001-NetherlandsHeartFoundation andUCLHospitalsNIHRBiomedicalResearchCentre. Publisher Copyright: © 2017 Brænne et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

PY - 2017/8/1

Y1 - 2017/8/1

N2 - 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.

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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U2 - 10.1371/journal.pone.0182999

DO - 10.1371/journal.pone.0182999

M3 - Article

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AN - SCOPUS:85028551507

SN - 1932-6203

VL - 12

JO - PLoS One

JF - PLoS One

IS - 8

M1 - e0182999

ER -

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

Abstract

Bibliographical note

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UN SDGs

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