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
N1 - Funding Information:
We thank the CARDIoGRAM and CARDIoGRAMplusC4D Consortium for contributing GWAS datasets. The study is supported by the German Federal Ministry of Education and Research (BMBF) in the context of the e:Med program (e:AtheroSysMed and sysINFLAME) and the FP7 European Union project CVgenes@ target (261123). Further grants were received by the Universität zu Lübeck, and by the Fondation Leducq (CADgenomics: Understanding Coronary Artery Disease Genes, 12CVD02). This study was also supported through the Deutsche Forschungsgemeinschaft (DFG) cluster of excellence ‘Inflammation at Interfaces (I.B.) and SFB 1123. T.K. was supported by a DZHK Rotation Grant. NJS holds a chair funded by the British Heart Foundation and is a NIHR Senior Investigator. Folkert W. Asselbergs is supported by a Dekker scholarship-Junior Staff Member 2014T001 – Netherlands Heart Foundation and UCL Hospitals NIHR Biomedical Research Centre. PWF reports grants from Sanofi Aventis, grants from Lilly, grants from Novo nordisk, personal fees from Sanofi Aventis, personal fees from Lilly. LW reports institutional research grants, consultancy fees, lecutre fees, and travel support from AstraZeneca, institutional research grants, consultancy fees, lecutre fees, and travel support from Boehringer Ingelheim, institutional research grants, consultancy fees, lecutre fees, and travel support from Bristol-Myers Squibb/Pfizer, grants from Merck & Co, grants from Roche, consultancy fees from Abbott and holds two patents involving GDF-15.
Publisher Copyright:
© 2017 The Author(s).
PY - 2017/12/1
Y1 - 2017/12/1
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.
UR - http://www.scopus.com/inward/record.url?scp=85028660363&partnerID=8YFLogxK
U2 - 10.1038/s41598-017-10928-4
DO - 10.1038/s41598-017-10928-4
M3 - Article
C2 - 28860667
AN - SCOPUS:85028660363
VL - 7
SP - 1
EP - 9
JO - Scientific Reports
JF - Scientific Reports
SN - 2045-2322
IS - 1
M1 - 10252
ER -