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Blood CSF1 and CXCL12 as Causal Mediators of Coronary Artery Disease
Jennifer Sjaarda1, Hertzel Gerstein2, Michael Chong3
1Population Health Research Institute, David Braley Cardiac, Vascular and Stroke Research Institute, Hamilton, Ontario, Canada; Thrombosis and Atherosclerosis Research Institute, David Braley Cardiac, Vascular and Stroke Research Institute, Hamilton, Ontario, Canada; Department of Pathology and Molecular Medicine, McMaster University, Michael G. DeGroote School of Medicine, Hamilton, Ontario, Canada.
Insights
This study used Mendelian randomization to identify novel causal biomarkers for coronary artery disease (CAD). Macrophage colony-stimulating factor 1 (CSF1) and stromal cell-derived factor 1 (CXCL12) were found to be causally linked to CAD.
Area of Science:
- Cardiovascular Research
- Genetics
- Biomarker Discovery
Background:
- Identifying biomarkers for coronary artery disease (CAD) aids prevention and treatment.
- Epidemiological studies may show associations due to reverse causation or confounding, not true causality.
- Mendelian randomization (MR) is a robust method to establish causal relationships.
Purpose of the Study:
- To conduct a comprehensive screen of 237 biomarkers using MR to identify causal mediators of CAD.
- To validate novel biomarker associations with CAD and major adverse cardiovascular events.
Main Methods:
- Utilized MR by analyzing genetic determinants of 227 biomarkers in ORIGIN trial participants (N=4,147).
- Combined biomarker genetic effects with CAD genetic effects from the CARDIoGRAM consortium (60,801 cases, 123,504 controls).
- Assessed associations of MR-identified biomarkers with incident major adverse cardiovascular events in ORIGIN and UK Biobank.
Main Results:
- Identified six biomarkers causally linked to CAD after multiple hypothesis testing.
- Macrophage colony-stimulating factor 1 (CSF1) and stromal cell-derived factor 1 (CXCL12) emerged as novel causal mediators.
- CSF1 showed an 18% higher CAD risk per SD increase (OR 1.18), with consistent epidemiological findings (HR 1.16). CXCL12 also demonstrated a causal role in CAD.
Conclusions:
- CSF1 and CXCL12 are identified as novel causal mediators of CAD in humans.
- Understanding their mechanisms offers new insights and potential prevention strategies for CAD.
- Results support targeting inflammatory processes, particularly macrophages, for CAD prevention, aligning with findings from CANTOS.
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).
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