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Circulating interleukins in relation to coronary artery disease, atrial fibrillation and ischemic stroke and its subtypes: A two-sample Mendelian randomization study.
International Journal of Cardiology ( IF 3.5 ) Pub Date : 2020-03-21 , DOI: 10.1016/j.ijcard.2020.03.053
Shuai Yuan 1 , Ang Lin 2 , Qi-Qiang He 3 , Stephen Burgess 4 , Susanna C Larsson 1
Affiliation  

Background

The causal role of interleukins (ILs) for cardiovascular disease has not been fully elucidated. We conducted a Mendelian randomization study to investigate the associations of circulating ILs with coronary artery disease (CAD), atrial fibrillation (AF), and ischemic stroke.

Methods and results

Single-nucleotide polymorphisms associated with IL-1β, IL-1 receptor antagonist (IL-1ra), IL-2 receptor subunit alpha, IL-6, IL-16, IL-17 and IL-18 were identified from genome-wide association studies. Summary-level data of the outcomes were obtained from three large consortia. Genetic predisposition to higher IL-1ra levels were significantly associated with CAD. The odds ratio was 1.36 (95% confidence interval (CI), 1.14–1.63; P = 5.37 × 10−4) per one standard deviation increase in IL-1ra levels. Genetically higher IL-6 levels, predicted by a variant in the IL6R gene and corresponding to reduced IL-6 bio-function, were significantly inversely associated with CAD and AF. The odds ratios per one standard deviation increase in IL-6 levels were 0.64 (95%CI, 0.54–0.76; P = 2.22 × 10−7) for CAD and 0.70 (95%CI, 0.62–0.80; P = 1.34 × 10−7) for AF. There was a suggestive positive association of IL-1ra with cardioembolic stroke and suggestive inverse associations of IL-6 with any ischemic stroke, cardioembolic stroke, and small vessel stroke, and of IL-16 with CAD. The other ILs were not associated with any outcome.

Conclusions

These results strengthen the evidence that IL-6 inhibition may offer a therapeutic approach for prevention of CAD, AF, and ischemic stroke. In contrast, IL-1 inhibition through raised IL-1ra levels may confer increased risk of CAD and cardioembolic stroke. The role of IL-16 for CAD warrants further investigation.



中文翻译:

与冠状动脉疾病、心房颤动和缺血性中风及其亚型相关的循环白细胞介素:一项两样本孟德尔随机化研究。

背景

白细胞介素 (ILs) 对心血管疾病的因果作用尚未完全阐明。我们进行了一项孟德尔随机化研究,以调查循环 ILs 与冠状动脉疾病 (CAD)、心房颤动 (AF) 和缺血性中风的关系。

方法和结果

从全基因组关联中鉴定出与 IL-1β、IL-1 受体拮抗剂 (IL-1ra)、IL-2 受体亚基 α、IL-6、IL-16、IL-17 和 IL-18 相关的单核苷酸多态性学习。结果的汇总级数据来自三个大型财团。较高 IL-1ra 水平的遗传易感性与 CAD 显着相关。IL-1ra 水平每增加一个标准差,优势比为 1.36(95% 置信区间 (CI),1.14–1.63;P  = 5.37 × 10 -4 )。由IL6R中的变体预测的遗传性更高的 IL-6 水平基因和对应于降低的 IL-6 生物功能,与 CAD 和 AF 显着负相关。IL-6 水平每增加一个标准差的优势比为 CAD 0.64 (95%CI, 0.54–0.76; P  = 2.22 × 10 -7 ) 和 0.70 (95%CI, 0.62–0.80; P  = 1.34 × 10 −7 ) 用于自动对焦。IL-1ra 与心源性卒中呈正相关,IL-6 与任何缺血性卒中、心源性卒中和小血管卒中呈负相关,IL-16 与 CAD 呈负相关。其他 ILs 与任何结果无关。

结论

这些结果加强了 IL-6 抑制可能为预防 CAD、AF 和缺血性中风提供治疗方法的证据。相反,通过提高 IL-1ra 水平来抑制 IL-1 可能会增加 CAD 和心源性卒中的风险。IL-16 对 CAD 的作用值得进一步研究。

更新日期:2020-03-21
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