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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 and Laakso, Markku, et al. (2017) In Scientific Reports 7(1).
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 ×... (More)

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.

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Scientific Reports
volume
7
issue
1
publisher
Nature Publishing Group
external identifiers
  • scopus:85028660363
  • wos:000408781200111
ISSN
2045-2322
DOI
10.1038/s41598-017-10928-4
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English
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yes
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a28a0372-b29f-418b-bd5b-9bdb8f008063
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2017-09-25 14:17:02
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2018-10-16 02:30:14
@article{a28a0372-b29f-418b-bd5b-9bdb8f008063,
  abstract     = {<p>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<sup>-5</sup> (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.</p>},
  articleno    = {10252},
  author       = {Brænne, Ingrid and Willenborg, Christina and Tragante, Vinicius and Kessler, Thorsten and Zeng, Lingyao and Reiz, Benedikt and Kleinecke, Mariana and Von Ameln, Simon and Willer, Cristen J and Laakso, Markku and Wild, Philipp S. and Zeller, Tanja and Wallentin, Lars and Franks, Paul W. and Salomaa, Veikko and Dehghan, Abbas and Meitinger, Thomas and Samani, Nilesh J. and Asselbergs, Folkert W and Erdmann, Jeanette and Schunkert, Heribert},
  issn         = {2045-2322},
  language     = {eng},
  month        = {12},
  number       = {1},
  publisher    = {Nature Publishing Group},
  series       = {Scientific Reports},
  title        = {A genomic exploration identifies mechanisms that may explain adverse cardiovascular effects of COX-2 inhibitors},
  url          = {http://dx.doi.org/10.1038/s41598-017-10928-4},
  volume       = {7},
  year         = {2017},
}