Author + information
- Received January 6, 2018
- Revision received March 26, 2018
- Accepted April 16, 2018
- Published online July 9, 2018.
- Jennifer Sjaarda, BScia,b,c,
- Hertzel Gerstein, MD, MSca,d,
- Michael Chong, MSca,b,e,
- Salim Yusuf, DPhila,
- David Meyre, PhDd,e,
- Sonia S. Anand, MD, PhDa,d,
- Sibylle Hess, PhDf and
- Guillaume Paré, MD, MSca,b,c,d,e,∗ (, )@McMasterU
- aPopulation Health Research Institute, David Braley Cardiac, Vascular and Stroke Research Institute, Hamilton, Ontario, Canada
- bThrombosis and Atherosclerosis Research Institute, David Braley Cardiac, Vascular and Stroke Research Institute, Hamilton, Ontario, Canada
- cDepartment of Pathology and Molecular Medicine, McMaster University, Michael G. DeGroote School of Medicine, Hamilton, Ontario, Canada
- dDepartment of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, Ontario, Canada
- eDepartment of Biochemistry, McMaster University, Hamilton, Ontario, Canada
- fSanofi Aventis Deutschland GmbH, Research and Development Division, Translational Medicine and Early Development, Biomarkers and Clinical Bioanalyses, Frankfurt, Germany
- ↵∗Address for correspondence:
Dr. Guillaume Paré, McMaster University, Population Health Research Institute, David Braley Cardiac, Vascular and Stroke Institute, 237 Barton Street East, C4-126, Hamilton, Ontario L8L 2X2, Canada.
Background Identification of biomarkers that cause coronary artery disease (CAD) has led to important advances in prevention and treatment. Epidemiological analyses have identified many biomarker-CAD relationships; however, these associations may arise from reverse causation and/or confounding and therefore may not represent true causal associations. Mendelian randomization (MR) analyses overcome these limitations.
Objectives This study sought to identify causal mediators of CAD through a comprehensive screen of 237 biomarkers using MR.
Methods MR was performed by identifying genetic determinants of 227 biomarkers in ORIGIN (Outcome Reduction With Initial Glargine Intervention) trial participants (N = 4,147) and combining these with genetic effects on CAD from the CARDIoGRAM consortium (60,801 cases and 123,504 controls). Blood concentrations of novel biomarkers identified by MR were then tested for association with incident major adverse cardiovascular events in ORIGIN.
Results Six biomarkers were found to be causally linked to CAD after adjustment for multiple hypothesis testing. The causal role of 4 of these is well documented, whereas macrophage colony-stimulating factor 1 (CSF1) and stromal cell–derived factor 1 (CXCL12) have not previously been reported, to the best of our knowledge. MR analysis predicted an 18% higher risk of CAD per SD increase in CSF1 (odds ratio: 1.18; 95% confidence interval: 1.08 to 1.30; p = 2.1 × 10−4) and epidemiological analysis identified a 16% higher risk of major adverse cardiovascular events per SD (hazard ratio: 1.16; 95% confidence interval: 1.09 to 1.23; p < 0.001). Elevated CXCL12 levels were also identified as a causal risk factor for CAD with consistent epidemiological results. Furthermore, genetically predicted CSF1 and CXCL12 levels were associated with CAD in the UK Biobank (n = 343,735).
Conclusions The study identified CSF1 and CXCL12 as causal mediators of CAD in humans. Understanding the mechanism by which these markers mediate CAD will provide novel insights into CAD and could lead to new approaches to prevention. These results support targeting inflammatory processes and macrophages, in particular, to prevent CAD, consistent with the recent CANTOS (Canakinumab Antiinflammatory Thrombosis Outcome Study). (Outcome Reduction With Initial Glargine Intervention [ORIGIN]; NCT00069784)
The ORIGIN trial and biomarker project were supported by Sanofi and the Canadian Institutes of Health Research (award 125794). Dr. Gerstein has received consulting fees from Sanofi, Novo Nordisk, Lilly, AstraZeneca, Boehringer Ingelheim, and GlaxoSmithKline; has received support for research or continuing education through his institution from Sanofi, Lilly, Takeda, Novo Nordisk, Boehringer Ingelheim, and AstraZeneca; and has received support from the Population Health Institute Chair in Diabetes Research and Care. Dr. Paré has received consulting fees from Sanofi, Bristol-Myers Squibb, Lexicomp, and Amgen; has received support for research through his institution from Sanofi; and has received support from the Canada Research Chair in Genetic and Molecular Epidemiology, CISCO Professorship in Integrated Health Systems. Dr. Hess is an employee of and owns stock in Sanofi. Dr. Yusuf has received research support for ORIGIN from Sanofi through his institution; and has received support from the Heart and Stroke Foundation of Ontario/Marion W. Burke Chair in Cardiovascular Disease. Dr. Anand has received support from the Canada Research Chair in Ethnicity and Cardiovascular Disease, Michael G. DeGroote Chair in Population Health. Dr. Meyre has received support from the Tier 2 Canada Research Chair in Genetics of Obesity. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Received January 6, 2018.
- Revision received March 26, 2018.
- Accepted April 16, 2018.
- 2018 American College of Cardiology Foundation
This article requires a subscription or purchase to view the full text. If you are a subscriber or member, click Login or the Subscribe link (top menu above) to access this article.