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Meta-Analysis
. 2024 Jun 28;100(1185):461-468.
doi: 10.1093/postmj/qgae017.

Genetic effects of inflammatory cytokines on coronary artery disease and myocardial infarction and the mediating roles of lipid traits

Affiliations
Meta-Analysis

Genetic effects of inflammatory cytokines on coronary artery disease and myocardial infarction and the mediating roles of lipid traits

Junsong Liu et al. Postgrad Med J. .

Abstract

Background: Chronic inflammation has been connected by epidemiological evidence to coronary artery disease (CAD) along with myocardial infarction (MI). Nevertheless, it is still unclear whether reverse causality or confounders account for these connections. Our objectives are to examine the causality between inflammatory cytokines and CAD/MI as well as the potential mediating influence of lipid characteristics.

Methods: We acquired instrumental variables through genome-wide association studies meta-analyses of 41 inflammatory cytokines (8293 individuals). Genetic associations with CAD (122 733 cases and 424 528 controls), MI (~61 505 cases and 577 716 controls) and five candidate lipid mediators were obtained from the corresponding genome-wide association studies. A two-step, two-sample Mendelian randomization analysis was applied, followed with comprehensive sensitivity analyses.

Results: Genetically determined growth regulated oncogene-α was causally linked to a decreased incidence of CAD [odds ratio (OR), 0.97; 95% confidence interval (CI), 0.95-0.99; P = .007] and MI (OR, 0.95; 95% CI, 0.92-0.98; P = .002). There is suggestive evidence indicating a causal impact of macrophage inflammatory protein-1β upon CAD (OR, 1.04; 95% CI, 1.01-1.07; P = .010) and MI (OR, 1.07; 95% CI, 1.02-1.11; P = .002). Furthermore, we discovered suggestive causal connections between tumor necrosis factor-related apoptosis-inducing ligand and CAD (OR, 0.97; 95% CI, 0.95-1.00; P = .020). Two-step Mendelian randomization analysis revealed that triglycerides partially mediate the effect of growth regulated oncogene-α on CAD (proportion-mediated: 13.28%) and MI (8.05%).

Conclusions: We provided novel genetic evidence supporting the causality of inflammatory cytokines on CAD/MI and elucidate the mediating effect of triglycerides in the causal pathways linking inflammatory cytokines and CAD/MI.

Keywords: Mendelian randomization; coronary artery disease; cytokines; lipid; myocardial infarction.

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