中性粒细胞胞外诱捕网可增加脓毒症发生风险——一项两样本单向孟德尔随机化研究

Neutrophil extracellular trap increase the risk of sepsis:a two-sample,one-way Mendelian randomization study

目的:基于孟德尔随机化分析方法,探讨中性粒细胞胞外诱捕网(NET)与脓毒症的因果关系。方法:选择基于Donkel等对荷兰鹿特丹研究(RS)分析结果的针对NET生物标志物髓过氧化物酶(MPO) -DNA复合体全基因组关联分析(GWAS)数据集,以及英国生物样本库(UK biobank)中识别脓毒症的相关GWAS数据集,以MPO-DNA复合体为暴露因素,筛选与MPO-DNA复合体相关的单核苷酸多态性(SNP)作为遗传变异工具变量(IV)。采用两样本单向孟德尔随机化主要分析方法逆方差分析法(IVW)分析MPO-DNA复合体与脓毒症、脓毒症28 d死亡、因脓毒症需重症监护、需重症监护的脓毒症28 d死亡的潜在因果关系。利用MR Egger回归截距检验评估SNP水平多效性;采用"leave one out"检验进行敏感性分析。结果:GWAS数据均来源于欧洲人群,男女不限,以孟德尔随机化三大假设为前提设置筛选标准,最终22个SNP纳入孟德尔随机化分析。采用IVW方法进行孟德尔随机化因果关联效应分析结果显示,MPO-DNA复合体水平每增加1个标准差,脓毒症发生风险上升约18%〔优势比( OR)=1.18,95%可信区间(95% CI)为1.07~1.29, P<0.001 〕,脓毒症28 d死亡风险上升约51%( OR=1.51,95% CI为1.27~1.81, P<0.001),因脓毒症需重症监护的风险上升约38%( OR=1.38,95% CI为1.12~1.70, P=0.002),需重症监护的脓毒症28 d死亡风险上升约125%( OR=2.25,95% CI为1.21~4.18, P=0.010);MR Egger回归截距检验提示纳入的SNP不存在水平多效性,MR-PRESSO检验未发现离群值;敏感性分析提示孟德尔随机化结果稳健。 结论:通过孟德尔随机化分析得出NET水平升高可增加脓毒症的发生、恶化及死亡风险。

ObjectiveTo investigate the causal relationship between neutrophil extracellular trap(NET)and sepsis based on Mendelian randomization analysis.MethodsThe genome wide association study(GWAS)dataset for the NET biomarker myeloperoxidase(MPO)-DNA complex based on Donkel et al.'s Rotterdam study(RS)and GWAS dataset for identifying sepsis from the UK biobank were selected to screen single nucleotide polymorphisms(SNPS)associated with MPO-DNA complex as instrumental variable(IV)for genetic variation,using MPO-DNA complex as exposure factor.Potential causal associations between MPO-DNA complex and the risk of occurrence of sepsis,28-day death from sepsis,need for intensive care due to sepsis,and 28-day death from sepsis requiring intensive care were analyzed using a two-sample,one-way Mendelian randomization analysis primary analysis method of inverse analysis of variance(IVW).Potential pleiotropy was assessed using the MR Egger regression intercept test.Sensitivity analysis was performed using the"leave one out"test.ResultsThe GWAS data were obtained from a European population of both sexes,and the screening criteria was based on the three main assumptions of Mendelian randomization,resulting in 22 SNP entering the Mendelian randomization analysis.The results of the Mendelian randomization causal association effect analysis using the IVW method showed that for every standard deviation increase in the level of the MPO-DNA complex,the risk of sepsis increased by approximately 18%[odds ratio(OR)=1.18,95%confidence interval(95%CI)was 1.07-1.29,P<0.001],the risk of 28-day death from sepsis increased by approximately 51%(OR=1.51,95%CI was 1.27-1.81,P<0.001),an increase of approximately 38%in the risk of occurrence of needing intensive care due to sepsis(OR=1.38,95%CI was 1.12-1.70,P=0.002),and an increase of approximately 125%in the risk of 28-day death from sepsis requiring intensive care(OR=2.25,95%CI was 1.21-4.18,P=0.01).MR Egger regression intercept test suggested that there was no horizontal pleiotropy in the included SNP,and the MR-PRESSO test did not find outliers.Sensitivity analysis suggested that the results of Mendelian randomization were robust.ConclusionRising NET can increase the risk of sepsis onset,progression and death as derived from Mendelian randomization analysis.