替格瑞洛与感染风险的关联:一项基于GWAS数据库的两样本孟德尔随机化研究

Association of ticagrelor with risk of infection:a two-sample Mendelian randomization study based on GWAS database

目的探讨替格瑞洛与感染风险的因果关联。方法采用两样本孟德尔随机化方法。基于迄今为止最大规模的替格瑞洛及其主要活性代谢物AR-C124910XX体内暴露量的全基因组关联分析结果选取遗传工具变量。通过逆方差加权法孟德尔随机化模型分析替格瑞洛及其主要活性代谢物AR-C124910XX与药物适应证(冠状动脉疾病、不稳定型心绞痛、心肌梗死、卒中和缺血性卒中)的因果关系,作为遗传工具变量的阳性控制内容。进一步使用该方法分析替格瑞洛与细菌感染、急性下呼吸道感染、细菌性肺炎、肺炎、急性上呼吸道感染、脓毒症的因果关系,并用异质性检验、水平基因多效性检验来评估结果的稳健性。结果遗传代理的替格瑞洛稳态药时曲线下面积(AUCss)增加可以显著降低冠状动脉疾病、心肌梗死、不稳定型心绞痛的发生风险(P<0.001),而其主要活性代谢物AR-C124910XX的AUCss遗传工具变量未能通过阳性控制。进一步分析显示,遗传代理的替格瑞洛AUCss的增加可以潜在地降低细菌感染[OR(95%CI)=0.80(0.65,0.99),P=0.040]和脓毒症[OR(95%CI)=0.84(0.73,0.98),P=0.023]的发生风险。异质性检验结果表明,遗传代理的替格瑞洛AUCss与细菌感染、脓毒症的因果关联不存在异质性(P>0.05)。水平基因多效性检验结果表明,遗传代理的替格瑞洛AUCss与细菌感染、脓毒症的因果关联不存在水平基因多效性的影响(P>0.05)。结论替格瑞洛具有潜在的降低脓毒症和细菌感染风险的作用。

OBJECTIVE To investigate the causal association between ticagrelor and risk of infection METHODS Two-sample Mendelian randomization was adopted.Genetic instrumental variables were selected based on the results of the largest genome-wide association analysis to in vivo exposure of ticagrelor and its major active metabolite AR-C124910XX.The causal associations of ticagrelor and its major active metabolite AR-C124910XX with drug indications(coronary artery disease,unstable angina pectoris,myocardial infarction,stroke and ischemic stroke)were analyzed by inverse variance weighted Mendelian randomization model as a positive control for genetic instrumental variables.The causal relationship between ticagrelor and bacterial infection,acute lower respiratory infection,bacterial pneumoniae,pneumoniae,acute upper respiratory infection and sepsis were further analyzed by using this method,and the robustness of the results was assessed by using heterogeneity tests and horizontal pleiotropy tests.RESULTS The increase of area under the curve at steady state(AUCss)of the genetic surrogated ticagrelor significantly reduced the risk of coronary artery disease,myocardial infarction and unstable angina pectoris(P<0.001).AUCss genetic instrument variables of its main active metabolite AR-C124910XX failed to pass positive control.Further analysis showed that the increase of the genetic surrogated ticagrelor exposure suggestively reduced the risk of bacterial infection[OR(95%CI)=0.80(0.65,0.99),P=0.040]and sepsis[OR(95%CI)=0.84(0.73,0.98),P=0.023].The results of the heterogeneity tests showed that there was no heterogeneity in the causal association of the genetic surrogated ticagrelor AUCss with bacterial infection and sepsis(P>0.05).The results of horizontal pleiotropy tests showed that the causal association of genetic surrogated ticagrelor AUCss with bacterial infection and sepsis had no effects on horizontal pleiotropy(P>0.05).CONCLUSIONS Ticagrelor has a potential role in reducing the risk of sepsis and bacterial infections.