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

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

Brænne, Ingrid (författare): University of Lübeck,Univ Lubeck, Inst Cardiogenet, Lubeck, Germany.;DZHK German Res Ctr Cardiovasc Res, Partner Site Hamburg Lubeck Kiel, Lubeck, Germany.;Univ Heart Ctr Lubeck, Lubeck, Germany.

Zeng, Lingyao (författare): Technical University of Munich,Tech Univ Munich, Deutsch Herzzentrum Munchen, Munich, Germany.

Willenborg, Christina (författare): University of Lübeck,Univ Lubeck, Inst Cardiogenet, Lubeck, Germany.

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Tragante, Vinicius (författare): Utrecht University,UMC Utrecht, Div Heart & Lungs, Dept Cardiol, Utrecht, Netherlands.

Kessler, Thorsten (författare): Technical University of Munich,Tech Univ Munich, Deutsch Herzzentrum Munchen, Munich, Germany.

Willer, Cristen J (författare): University of Michigan,Univ Michigan, Dept Biostat, 1415 Washington Hts, Ann Arbor, MI USA.

Laakso, Markku (författare): University of Eastern Finland,Univ Eastern Finland, Internal Med, Inst Clin Med, Kuopio, Finland.;Kuopio Univ Hosp, Kuopio, Finland.

Wallentin, Lars (författare): Uppsala universitet,Uppsala University,Uppsala kliniska forskningscentrum (UCR)

Franks, Paul W (författare): Lund University,Lunds universitet,Genetisk och molekylär epidemiologi,Forskargrupper vid Lunds universitet,Genetic and Molecular Epidemiology,Lund University Research Groups,Lund Univ, Skane Univ Hosp Malmo, Genet & Mol Epidemiol Unit, Dept Clin Sci, Malmo, Sweden.

Salomaa, Veikko (författare): Finnish National Institute for Health and Welfare,THL Natl Inst Hlth & Welf, POB 30,Mannerheimintie 166, Helsinki, Finland.

Dehghan, Abbas (författare): Erasmus University Medical Center,Erasmus MC, Dept Epidemiol, Ca Rotterdam, Netherlands.

Meitinger, Thomas (författare): Technical University of Munich,Helmholtz Zentrum Munchen, Inst Human Genet, German Res Ctr Environm Hlth, Neuherberg, Germany.;DZHK German Ctr Cardiovasc Res, Partner Site Munich Heart Alliance, Munich, Germany.;Tech Univ Munich, Inst Human Genet, Munich, Germany.

Samani, Nilesh J. (författare): Glenfield Hospital,University of Leicester,Univ Leicester, Dept Cardiovasc Sci, Leicester, Leics, England.;Glenfield Hosp, NIHR Leicester Cardiovasc Biomed Res Unit, Leicester, Leics, England.

Asselbergs, Folkert W (författare): University College London,UMC Utrecht, Div Heart & Lungs, Dept Cardiol, Utrecht, Netherlands.;Netherlands Heart Inst, Durrer Ctr Cardiovasc Res, Utrecht, Netherlands.;UCL, Fac Populat Hlth Sci, Inst Cardiovasc Sci, London, England.

Erdmann, Jeanette (författare): University Heart Center Lübeck,Univ Lubeck, Inst Cardiogenet, Lubeck, Germany.;DZHK German Res Ctr Cardiovasc Res, Partner Site Hamburg Lubeck Kiel, Lubeck, Germany.;Univ Heart Ctr Lubeck, Lubeck, Germany.

Schunkert, Heribert (författare): German Centre for Cardiovascular Research,Tech Univ Munich, Deutsch Herzzentrum Munchen, Munich, Germany.;DZHK German Ctr Cardiovasc Res, Partner Site Munich Heart Alliance, Munich, Germany.

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University of Lübeck Univ Lubeck, Inst Cardiogenet, Lubeck, Germany;DZHK German Res Ctr Cardiovasc Res, Partner Site Hamburg Lubeck Kiel, Lubeck, Germany.;Univ Heart Ctr Lubeck, Lubeck, Germany. (creator_code:org_t)

2017-08-22
2017
Engelska.
Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 12:8, s. 0182999-0182999

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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 = 1.58×10-12). 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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Av författaren/redakt...: Brænne, Ingrid; Zeng, Lingyao; Willenborg, Chri ...; Tragante, Vinici ...; Kessler, Thorste ...; Willer, Cristen ...; visa fler...; Laakso, Markku; Wallentin, Lars; Franks, Paul W; Salomaa, Veikko; Dehghan, Abbas; Meitinger, Thoma ...; Samani, Nilesh J ...; Asselbergs, Folk ...; Erdmann, Jeanett ...; Schunkert, Herib ...; visa färre...

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Artiklar i publikationen: PLoS ONE

Av lärosätet: Lunds universitet; Uppsala universitet

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

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