Circulating cytokines and alcoholic liver disease: a two-sample bidirectional Mendelian randomization study

Increased inflammation in the liver during ethanol exposure is a major feature of alcoholic liver disease (ALD). An important contributing component to the development of ALD is the inflammatory response brought on by immunological response, however the connection between individual circulating cytokines and ALD is still unclear. To ascertain the causation, we conducted a two-sample bidirectional Mendelian randomization research. We extracted 41 cytokines and growth factors of 8293 Europeans and ALD cases of the same ethnicity (1416 cases and 217,376 controls) from the Genome-Wide Association Studies (GWAS) database for two-sample bidirectional MR analysis. Our analyses suggest that higher interleukin-7 (IL-7) levels are associated with an increased risk of ALD (p = 0.028, OR = 1.191,95% CI = 1.019–1.392), while tumor necrosis factor related apoptosis inducing ligand (TRAIL) is a protective factor for ALD (p = 0.032, OR = 0.863, 95% CI = 0.754–0.988) which can reduce the risk of disease occurrence. In addition, genetically predicted ALD does not affect the expression of circulating cytokines regulators. Our study supports that cytokines play a pivotal role in the pathogenesis of ALD. To determine the mechanisms and pathways of action of these biomarkers, further basic research is required to ensure their clinical suitability for preventing and treating ALD.

乙醇暴露期间肝脏炎症水平升高是酒精性肝病（alcoholic liver disease, ALD）的核心临床特征。免疫应答介导的炎症反应是ALD发生发展的重要致病环节，但循环中单个细胞因子与ALD的关联机制仍未阐明。为明确二者的因果关系，我们开展了双样本双向孟德尔随机化（two-sample bidirectional Mendelian randomization）研究。我们从全基因组关联研究（Genome-Wide Association Studies, GWAS）数据库中，获取了8293名欧洲裔个体的41种细胞因子及生长因子数据，以及同种族的ALD病例数据（1416例患者，217376例对照），用于开展双样本双向孟德尔随机化分析。分析结果表明，较高的白细胞介素7（interleukin-7, IL-7）水平与ALD发病风险升高显著相关（p=0.028，比值比（OR）=1.191，95%置信区间（CI）=1.019~1.392）；而肿瘤坏死因子相关凋亡诱导配体（tumor necrosis factor related apoptosis inducing ligand, TRAIL）则为ALD的保护性因素（p=0.032，OR=0.863，95%CI=0.754~0.988），可降低疾病发生风险。此外，通过遗传预测的ALD并不会影响循环细胞因子调控因子的表达水平。本研究证实细胞因子在ALD的发病机制中发挥关键作用。为明确上述生物标志物的作用机制与信号通路，需开展进一步基础研究以验证其在ALD防治中的临床适用性。