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

CARDIoGRAM; The CARDIOGRAMplusC4D Consortium; MuTHER Consortium; Wellcome Trust Case Control Consortium; Ingrid Brænne; Lingyao Zeng; Christina Willenborg; Vinicius Tragante; Thorsten Kessler; Cristen J. Willer; Markku Laakso; Lars Wallentin; Paul W. Franks; Veikko Salomaa; Abbas Dehghan; Thomas Meitinger; Nilesh J. Samani; Folkert W. Asselbergs; Jeanette Erdmann; Heribert Schunkert; Panos Deloukas; Stavroula Kanoni; Christina Willenborg; Martin Farrall; Themistocles L. Assimes; John R. Thompson; Erik Ingelsson; Danish Saleheen; Jeanette Erdmann; Benjamin A. Goldstein; Kathleen Stirrups; Inke R. König; Jean Baptiste Cazier; Åsa Johansson; Alistair Hall; Jong Young Lee; Cristen J. Willer; John C. Chambers; Tõnu Esko; Lasse Folkersen; Anuj Goel; Elin Grundberg; Aki S. Havulinna; Weang K. Ho; Jemma C. Hopewell; Christof Burgdorf; Thorsten Kessler; Seraya Maouche; Patrick Diemert; Heribert Schunkert; Jeanette Erdmann; Inke R. König; Heribert Schunkert; Andreas Ziegler

doi:10.1371/journal.pone.0182999

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

CARDIoGRAM, The CARDIOGRAMplusC4D Consortium, MuTHER Consortium, Wellcome Trust Case Control Consortium, Ingrid Brænne, Lingyao Zeng, Christina Willenborg, Vinicius Tragante, Thorsten Kessler, Cristen J. Willer, Markku Laakso, Lars Wallentin, Paul W. Franks, Veikko Salomaa, Abbas Dehghan, Thomas Meitinger, Nilesh J. Samani, Folkert W. Asselbergs, Jeanette Erdmann, Heribert SchunkertPanos Deloukas, Stavroula Kanoni, Christina Willenborg, Martin Farrall, Themistocles L. Assimes, John R. Thompson, Erik Ingelsson, Danish Saleheen, Jeanette Erdmann, Benjamin A. Goldstein, Kathleen Stirrups, Inke R. König, Jean Baptiste Cazier, Åsa Johansson, Alistair Hall, Jong Young Lee, Cristen J. Willer, John C. Chambers, Tõnu Esko, Lasse Folkersen, Anuj Goel, Elin Grundberg, Aki S. Havulinna, Weang K. Ho, Jemma C. Hopewell, Christof Burgdorf, Thorsten Kessler, Seraya Maouche, Patrick Diemert, Heribert Schunkert, Jeanette Erdmann, Inke R. König, Heribert Schunkert, Andreas Ziegler

5 Zitate (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.

Originalsprache	Englisch
Aufsatznummer	e0182999
Zeitschrift	PLoS ONE
Jahrgang	12
Ausgabenummer	8
ISSN	1553-7390
DOIs	https://doi.org/10.1371/journal.pone.0182999
Publikationsstatus	Veröffentlicht - 01.08.2017

Fördermittel

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.

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10.1371/journal.pone.0182999

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CARDIoGRAM, The CARDIOGRAMplusC4D Consortium, MuTHER Consortium, Wellcome Trust Case Control Consortium, Brænne, I., Zeng, L., Willenborg, C., Tragante, V., Kessler, T., Willer, C. J., Laakso, M., Wallentin, L., Franks, P. W., Salomaa, V., Dehghan, A., Meitinger, T., Samani, N. J., Asselbergs, F. W., Erdmann, J., ... Ziegler, A. (2017). Genomic correlates of glatiramer acetate adverse cardiovascular effects lead to a novel locus mediating coronary risk. PLoS ONE, 12(8), Artikel e0182999. https://doi.org/10.1371/journal.pone.0182999

@article{f054f3c68fd24c85806e3b5ed2a4570a,

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 and \{The 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 Christina Willenborg and Martin Farrall and Assimes, \{Themistocles L.\} and Thompson, \{John R.\} and Erik Ingelsson and Danish Saleheen and Jeanette Erdmann and Goldstein, \{Benjamin A.\} and Kathleen Stirrups and K{\"o}nig, \{Inke R.\} and Cazier, \{Jean Baptiste\} and {\AA}sa Johansson and Alistair Hall and Lee, \{Jong Young\} and Willer, \{Cristen J.\} 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 Christof Burgdorf and Thorsten Kessler and Seraya Maouche and Patrick Diemert and Heribert Schunkert and Jeanette Erdmann and K{\"o}nig, \{Inke R.\} and Heribert Schunkert and Andreas Ziegler",

year = "2017",

month = aug,

day = "1",

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

language = "English",

volume = "12",

journal = "PLoS ONE",

issn = "1553-7390",

publisher = "Public Library of Science",

number = "8",

}

CARDIoGRAM, The CARDIOGRAMplusC4D Consortium, MuTHER Consortium, Wellcome Trust Case Control Consortium, Brænne, I, Zeng, L, Willenborg, C, Tragante, V, Kessler, T, Willer, CJ, Laakso, M, Wallentin, L, Franks, PW, Salomaa, V, Dehghan, A, Meitinger, T, Samani, NJ, Asselbergs, FW, Erdmann, J, Schunkert, H, Deloukas, P, Kanoni, S, Willenborg, C, Farrall, M, Assimes, TL, Thompson, JR, Ingelsson, E, Saleheen, D, Erdmann, J, Goldstein, BA, Stirrups, K, König, IR, Cazier, JB, Johansson, Å, Hall, A, Lee, JY, Willer, CJ, Chambers, JC, Esko, T, Folkersen, L, Goel, A, Grundberg, E, Havulinna, AS, Ho, WK, Hopewell, JC, Burgdorf, C, Kessler, T, Maouche, S, Diemert, P, Schunkert, H, Erdmann, J, König, IR, Schunkert, H & Ziegler, A 2017, 'Genomic correlates of glatiramer acetate adverse cardiovascular effects lead to a novel locus mediating coronary risk', PLoS ONE, Jg. 12, Nr. 8, e0182999. https://doi.org/10.1371/journal.pone.0182999

TY - JOUR

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

AU - CARDIoGRAM

AU - The 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 - Willenborg, Christina

AU - Farrall, Martin

AU - Assimes, Themistocles L.

AU - Thompson, John R.

AU - Ingelsson, Erik

AU - Saleheen, Danish

AU - Erdmann, Jeanette

AU - Goldstein, Benjamin A.

AU - Stirrups, Kathleen

AU - König, Inke R.

AU - Cazier, Jean Baptiste

AU - Johansson, Åsa

AU - Hall, Alistair

AU - Lee, Jong Young

AU - Willer, Cristen J.

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 - Burgdorf, Christof

AU - Kessler, Thorsten

AU - Maouche, Seraya

AU - Diemert, Patrick

AU - Schunkert, Heribert

AU - Erdmann, Jeanette

AU - König, Inke R.

AU - Schunkert, Heribert

AU - Ziegler, Andreas

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.

UR - https://www.scopus.com/pages/publications/85028551507

U2 - 10.1371/journal.pone.0182999

DO - 10.1371/journal.pone.0182999

M3 - Journal articles

C2 - 28829817

AN - SCOPUS:85028551507

SN - 1553-7390

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

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