Cardiovascular Department, The First Affiliated Hospital of Harbin Medical University, Harbin, China.
Cardiovascular Department, the Fourth Affiliated Hospital of Harbin Medical University, Harbin, China.
Med Chem. 2020;16(5):626-634. doi: 10.2174/1573406415666191004115128.
Observational studies support the inflammation hypothesis in coronary heart disease (CHD). As a pleiotropic proinflammatory cytokine, Interleukin-18 (IL-18), has also been found to be associated with the risk of CHD. However, to our knowledge, the method of Mendelian Randomization has not been used to explore the causal effect of IL-18 on CHD.
To assess the causal effect of IL-18 on the risk of CHD.
Genetic variant instruments for IL-18 were obtained from information of the CHS and InCHIANTI cohort, and consisted of the per-allele difference in mean IL-18 for 16 independent variants that reached genome-wide significance. The per-allele difference in log-odds of CHD for each of these variants was estimated from CARDIoGRAMplusC4D, a two-stage meta -analysis. Two-sample Mendelian Randomization (MR) was then performed. Various MR analyses were used, including weighted inverse-variance, MR-Egger regression, robust regression, and penalized regression. The OR of elevated IL-18 associated with CHD was only 0.005 (95%CI -0.105~0.095; P-value=0.927). Similar results were obtained with the use of MR-Egger regression, suggesting that directional pleiotropy was unlikely biasing these results (intercept -0.050, P-value=0.220). Moreover, results from the robust regression and penalized regression analyses also revealed essentially similar findings.
Our findings indicate that, by itself, IL-18 is unlikely to represent even a modest causal factor for CHD risk.
观察性研究支持冠心病（CHD）中的炎症假说。白细胞介素-18（IL-18）作为一种多效性促炎细胞因子，也被发现与 CHD 的风险相关。然而，据我们所知，孟德尔随机化方法尚未用于探索 IL-18 对 CHD 的因果效应。
评估 IL-18 对 CHD 风险的因果影响。
从 CHS 和 InCHIANTI 队列的信息中获得了用于 IL-18 的遗传变异工具，这些工具由达到全基因组显著水平的 16 个独立变异的每个等位基因差异组成。从 CARDIoGRAMplusC4D 中估计了每个变异的 CHD 对数优势的等位基因差异，这是一个两阶段荟萃分析。然后进行了两样本孟德尔随机化（MR）。使用了各种 MR 分析，包括加权逆方差、MR-Egger 回归、稳健回归和惩罚回归。与 CHD 相关的升高的 IL-18 的 OR 仅为 0.005（95%CI -0.105~0.095；P 值=0.927）。使用 MR-Egger 回归也得到了相似的结果，这表明定向 pleiotropy 不太可能使这些结果产生偏差（截距-0.050，P 值=0.220）。此外，稳健回归和惩罚回归分析的结果也揭示了基本相似的发现。
我们的研究结果表明，单独的 IL-18 不太可能代表 CHD 风险的适度因果因素。
