期刊
JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY
卷 72, 期 3, 页码 300-310出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.jacc.2018.04.067
关键词
biomarker; coronary artery disease; CSF1; CXCL12; genetics; Mendelian randomization
资金
- Sanofi
- Canadian Institutes of Health Research [125794]
- Novo Nordisk
- Lilly
- AstraZeneca
- Boehringer Ingelheim
- GlaxoSmithKline
- Takeda
- Population Health Institute Chair in Diabetes Research and Care
- Canada Research Chair in Genetic and Molecular Epidemiology, CISCO Professorship in Integrated Health Systems
- ORIGIN from Sanofi through his institution
- Heart and Stroke Foundation of Ontario/Marion W. Burke Chair in Cardiovascular Disease
- Canada Research Chair in Ethnicity and Cardiovascular Disease, Michael G. DeGroote Chair in Population Health
- Tier 2 Canada Research Chair in Genetics of Obesity
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 x 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) (C) 2018 by the American College of Cardiology Foundation.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据