孟德尔随机化探究细胞因子与慢性肾脏病的因果关系

Causal association between cytokines and chronic kidney disease based on Mendelian randomization

目的 采用孟德尔随机化(Mendelian randomization, MR)方法探究细胞因子与慢性肾脏病(chronic kidney disease, CKD)的因果关系。方法 从全基因组关联分析(genome-wide association studies, GWAS)中获取研究数据,选择相互独立且与细胞因子相关的遗传位点作为工具变量(instrumental variables, IVs)。以逆方差加权法(inverse variance weighted, IVW)为主要方法,加权中位数法(Weighted Median)、MR Egger回归为补充进行MR分析。敏感性分析采用MR Egger截距项检验、留一法分析和Cochran's Q检验。并用Bonferroni法进行校正。当P<0.055×10^(-2)(0.050/91)时,结果具有显著的因果关系;当0.055×10^(-2)≤P<0.050时,结果具有潜在的因果关系。结果 共发现10种炎症因子与CKD有显著或潜在的关联。与CKD存在正向因果关联的有6种,显著相关的为IL-17C(IVW对应的OR=1.171,95%CI:1.079~1.270,P=1.426×10^(-4)),潜在相关的为IL-17A、CXCL10、MCP-4、DNER、CCL-4;与CKD存在负向因果关联的有4种,无显著相关,潜在相关的为CD40R、CD244、OPG、MIP-1a;敏感性分析证实了研究结果的准确性和稳健性。结论 IL-17C显著增加CKD的风险,IL-17A、CXCL10、MCP-4、DNER、CCL-4可能增加CKD的风险,CD40R、CD244、OPG、MIP-1a可能降低CKD的风险。

Objective To explore the causal relationship between cytokines and chronic kidney disease(CKD)using the Mendelian randomization(MR)analysis.Methods Data for the analysis were sourced from genome-wide association studies(GWAS)and independent genetic loci associated with cytokines were selected as instrumental variables(IVs).MR analysis was conducted primarily using the inverse variance weighted(IVW)method,complemented by the Weighted Median and MR Egger regression approaches.Sensitivity analysis was performed using MR Egger regression intercept term test,leave-one-out analysis,and Cochrans Q tests.The Bonferroni correction was applied and the results were considered significantly causal when P<0.055×10^(-2)(0.050/91),and potentially causal when 0.055×10^(-2)≤P<0.050.Results A total of 10 inflammatory factors were identified as significantly or potentially associated with CKD.Six cytokines showed positive causal associations with CKD,with IL-17C being significantly associated(for IVW,OR=1.171,95%CI:1.079-1.270,P=1.426×10^(-4)).Cytokines potentially associated with increased risk of CKD included IL-17A,CXCL10,MCP-4,DNER,and CCL-4.Four cytokines demonstrated negative causal associations with CKD,although none were significantly correlated.CD40R,CD244,OPG,and MIP-1a were potentially associated with a reduced risk of CKD included.The precision and robustness of the findings were confirmed by sensitivity tests.Conclusion IL-17C significantly increases the risk of CKD,while IL-17A,CXCL10,MCP-4,DNER and CCL-4 may increase the risk of CKD.In contrast,CD40R,CD244,OPG,and MIP-1a may lower the risk of CKD.