Liu Junsong, Ying Jiajun, Hu Teng
Department of Cardiology, The First Affiliated Hospital of Ningbo University, School of Medicine, Ningbo University, Ningbo, Zhejiang 315010, China.
Cardiovascular Disease Clinical Medical Research Center of Ningbo, Ningbo, Zhejiang 315010, China.
Postgrad Med J. 2024 Jun 28;100(1185):461-468. doi: 10.1093/postmj/qgae017.
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.
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.
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%).
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.
流行病学证据表明，慢性炎症与冠状动脉疾病（CAD）以及心肌梗死（MI）相关。然而，这些关联是由反向因果关系还是混杂因素导致仍不清楚。我们的目标是研究炎性细胞因子与CAD/MI之间的因果关系以及脂质特征的潜在中介作用。
我们通过对41种炎性细胞因子（8293名个体）的全基因组关联研究荟萃分析获得工具变量。从相应的全基因组关联研究中获取与CAD（122733例病例和424528例对照）、MI（约61505例病例和577716例对照）以及五种候选脂质介质的遗传关联。应用两步两样本孟德尔随机化分析，并进行全面的敏感性分析。
基因决定的生长调节致癌基因-α与CAD发病率降低存在因果关系[比值比（OR），0.97；95%置信区间（CI），0.95 - 0.99；P = 0.007]以及MI（OR，0.95；95% CI，0.92 - 0.98；P = 0.002）。有提示性证据表明巨噬细胞炎性蛋白-1β对CAD（OR，1.04；95% CI，1.01 - 1.07；P = 0.010）和MI（OR，1.07；95% CI，1.02 - 1.11；P = 0.002）有因果影响。此外，我们发现肿瘤坏死因子相关凋亡诱导配体与CAD之间存在提示性因果关联（OR，0.97；95% CI，0.95 - 1.00；P = 0.020）。两步孟德尔随机化分析表明，甘油三酯部分介导生长调节致癌基因-α对CAD（介导比例：13.28%）和MI（8.05%）的影响。
我们提供了新的遗传证据，支持炎性细胞因子对CAD/MI的因果关系，并阐明了甘油三酯在连接炎性细胞因子与CAD/MI的因果途径中的中介作用。
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