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A genomic exploration identifies mechanisms that may explain adverse cardiovascular effects of COX-2 inhibitors

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A genomic exploration identifies mechanisms that may explain adverse cardiovascular effects of COX-2 inhibitors. / Brænne, Ingrid; Willenborg, Christina; Tragante, Vinicius; Kessler, Thorsten; Zeng, Lingyao; Reiz, Benedikt; Kleinecke, Mariana; von Ameln, Simon; Willer, Cristen J; Laakso, Markku; Wild, Philipp S; Zeller, Tanja; Wallentin, Lars; Franks, Paul W; Salomaa, Veikko; Dehghan, Abbas; Meitinger, Thomas; Samani, Nilesh J; Asselbergs, Folkert W; Erdmann, Jeanette; Schunkert, Heribert.

In: SCI REP-UK, Vol. 7, No. 1, 31.08.2017, p. 10252.

Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review

Harvard

Brænne, I, Willenborg, C, Tragante, V, Kessler, T, Zeng, L, Reiz, B, Kleinecke, M, von Ameln, S, Willer, CJ, Laakso, M, Wild, PS, Zeller, T, Wallentin, L, Franks, PW, Salomaa, V, Dehghan, A, Meitinger, T, Samani, NJ, Asselbergs, FW, Erdmann, J & Schunkert, H 2017, 'A genomic exploration identifies mechanisms that may explain adverse cardiovascular effects of COX-2 inhibitors', SCI REP-UK, vol. 7, no. 1, pp. 10252. https://doi.org/10.1038/s41598-017-10928-4

APA

Brænne, I., Willenborg, C., Tragante, V., Kessler, T., Zeng, L., Reiz, B., Kleinecke, M., von Ameln, S., Willer, C. J., Laakso, M., Wild, P. S., Zeller, T., Wallentin, L., Franks, P. W., Salomaa, V., Dehghan, A., Meitinger, T., Samani, N. J., Asselbergs, F. W., ... Schunkert, H. (2017). A genomic exploration identifies mechanisms that may explain adverse cardiovascular effects of COX-2 inhibitors. SCI REP-UK, 7(1), 10252. https://doi.org/10.1038/s41598-017-10928-4

Vancouver

Brænne I, Willenborg C, Tragante V, Kessler T, Zeng L, Reiz B et al. A genomic exploration identifies mechanisms that may explain adverse cardiovascular effects of COX-2 inhibitors. SCI REP-UK. 2017 Aug 31;7(1):10252. https://doi.org/10.1038/s41598-017-10928-4

Bibtex

@article{eca36c0a9a1a4747b3cf34705e571256,
title = "A genomic exploration identifies mechanisms that may explain adverse cardiovascular effects of COX-2 inhibitors",
abstract = "Cyclooxygenase-2 inhibitors (coxibs) are characterized by multiple molecular off-target effects and increased coronary artery disease (CAD) risk. Here, we systematically explored common variants of genes representing molecular targets of coxibs for association with CAD. Given a broad spectrum of pleiotropic effects of coxibs, our intention was to narrow potential mechanisms affecting CAD risk as we hypothesized that the affected genes may also display genomic signals of coronary disease risk. A Drug Gene Interaction Database search identified 47 gene products to be affected by coxibs. We traced association signals in 200-kb regions surrounding these genes in 84,813 CAD cases and 202,543 controls. Based on a threshold of 1 × 10-5 (Bonferroni correction for 3131 haplotype blocks), four gene loci yielded significant associations. The lead SNPs were rs7270354 (MMP9), rs4888383 (BCAR1), rs6905288 (VEGFA1), and rs556321 (CACNA1E). By additional genotyping, rs7270354 at MMP9 and rs4888383 at BCAR1 also reached the established GWAS threshold for genome-wide significance. The findings demonstrate overlap of genes affected by coxibs and those mediating CAD risk and points to further mechanisms, which are potentially responsible for coxib-associated CAD risk. The novel approach furthermore suggests that genetic studies may be useful to explore the clinical relevance of off-target drug effects.",
keywords = "Cardiotoxicity/etiology, Chromosome Mapping, Computational Biology/methods, Cyclooxygenase 2 Inhibitors/adverse effects, Databases, Genetic, Databases, Pharmaceutical, Gene Expression Profiling, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Pharmacogenetics/methods, Polymorphism, Single Nucleotide",
author = "Ingrid Br{\ae}nne and Christina Willenborg and Vinicius Tragante and Thorsten Kessler and Lingyao Zeng and Benedikt Reiz and Mariana Kleinecke and {von Ameln}, Simon and Willer, {Cristen J} and Markku Laakso and Wild, {Philipp S} and Tanja Zeller 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",
year = "2017",
month = aug,
day = "31",
doi = "10.1038/s41598-017-10928-4",
language = "English",
volume = "7",
pages = "10252",
journal = "SCI REP-UK",
issn = "2045-2322",
publisher = "NATURE PUBLISHING GROUP",
number = "1",

}

RIS

TY - JOUR

T1 - A genomic exploration identifies mechanisms that may explain adverse cardiovascular effects of COX-2 inhibitors

AU - Brænne, Ingrid

AU - Willenborg, Christina

AU - Tragante, Vinicius

AU - Kessler, Thorsten

AU - Zeng, Lingyao

AU - Reiz, Benedikt

AU - Kleinecke, Mariana

AU - von Ameln, Simon

AU - Willer, Cristen J

AU - Laakso, Markku

AU - Wild, Philipp S

AU - Zeller, Tanja

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

PY - 2017/8/31

Y1 - 2017/8/31

N2 - Cyclooxygenase-2 inhibitors (coxibs) are characterized by multiple molecular off-target effects and increased coronary artery disease (CAD) risk. Here, we systematically explored common variants of genes representing molecular targets of coxibs for association with CAD. Given a broad spectrum of pleiotropic effects of coxibs, our intention was to narrow potential mechanisms affecting CAD risk as we hypothesized that the affected genes may also display genomic signals of coronary disease risk. A Drug Gene Interaction Database search identified 47 gene products to be affected by coxibs. We traced association signals in 200-kb regions surrounding these genes in 84,813 CAD cases and 202,543 controls. Based on a threshold of 1 × 10-5 (Bonferroni correction for 3131 haplotype blocks), four gene loci yielded significant associations. The lead SNPs were rs7270354 (MMP9), rs4888383 (BCAR1), rs6905288 (VEGFA1), and rs556321 (CACNA1E). By additional genotyping, rs7270354 at MMP9 and rs4888383 at BCAR1 also reached the established GWAS threshold for genome-wide significance. The findings demonstrate overlap of genes affected by coxibs and those mediating CAD risk and points to further mechanisms, which are potentially responsible for coxib-associated CAD risk. The novel approach furthermore suggests that genetic studies may be useful to explore the clinical relevance of off-target drug effects.

AB - Cyclooxygenase-2 inhibitors (coxibs) are characterized by multiple molecular off-target effects and increased coronary artery disease (CAD) risk. Here, we systematically explored common variants of genes representing molecular targets of coxibs for association with CAD. Given a broad spectrum of pleiotropic effects of coxibs, our intention was to narrow potential mechanisms affecting CAD risk as we hypothesized that the affected genes may also display genomic signals of coronary disease risk. A Drug Gene Interaction Database search identified 47 gene products to be affected by coxibs. We traced association signals in 200-kb regions surrounding these genes in 84,813 CAD cases and 202,543 controls. Based on a threshold of 1 × 10-5 (Bonferroni correction for 3131 haplotype blocks), four gene loci yielded significant associations. The lead SNPs were rs7270354 (MMP9), rs4888383 (BCAR1), rs6905288 (VEGFA1), and rs556321 (CACNA1E). By additional genotyping, rs7270354 at MMP9 and rs4888383 at BCAR1 also reached the established GWAS threshold for genome-wide significance. The findings demonstrate overlap of genes affected by coxibs and those mediating CAD risk and points to further mechanisms, which are potentially responsible for coxib-associated CAD risk. The novel approach furthermore suggests that genetic studies may be useful to explore the clinical relevance of off-target drug effects.

KW - Cardiotoxicity/etiology

KW - Chromosome Mapping

KW - Computational Biology/methods

KW - Cyclooxygenase 2 Inhibitors/adverse effects

KW - Databases, Genetic

KW - Databases, Pharmaceutical

KW - Gene Expression Profiling

KW - Genetic Predisposition to Disease

KW - Genome-Wide Association Study

KW - Humans

KW - Pharmacogenetics/methods

KW - Polymorphism, Single Nucleotide

U2 - 10.1038/s41598-017-10928-4

DO - 10.1038/s41598-017-10928-4

M3 - SCORING: Journal article

C2 - 28860667

VL - 7

SP - 10252

JO - SCI REP-UK

JF - SCI REP-UK

SN - 2045-2322

IS - 1

ER -