Wang Jian, Zhang Yan, Cheng Lu, Geng Yanxia, Lu Jun, Zhou Jiang
Department of Intensive Care Unit, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing 210029, Jiangsu, China. Corresponding author: Zhou Jiang, Email:
Zhonghua Wei Zhong Bing Ji Jiu Yi Xue. 2023 Oct;35(10):1045-1052. doi: 10.3760/cma.j.cn121430-20230117-00030.
To investigate the causal relationship between neutrophil extracellular trap (NET) and sepsis based on Mendelian randomization analysis.
The 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.
The 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.
Rising NET can increase the risk of sepsis onset, progression and death as derived from Mendelian randomization analysis.
基于孟德尔随机化分析探讨中性粒细胞胞外陷阱（NET）与脓毒症之间的因果关系。
选取基于唐克尔等人的鹿特丹研究（RS）的NET生物标志物髓过氧化物酶（MPO）-DNA复合物的全基因组关联研究（GWAS）数据集以及来自英国生物银行的用于识别脓毒症的GWAS数据集，以筛选与MPO-DNA复合物相关的单核苷酸多态性（SNPs）作为遗传变异的工具变量（IV），将MPO-DNA复合物作为暴露因素。使用双样本单向孟德尔随机化分析的主要分析方法方差逆分析（IVW），分析MPO-DNA复合物与脓毒症发生风险、脓毒症28天死亡率、因脓毒症需要重症监护以及因脓毒症需要重症监护的28天死亡率之间的潜在因果关联。使用MR Egger回归截距检验评估潜在的多效性。使用“留一法”检验进行敏感性分析。
GWAS数据来自欧洲男女混合人群，筛选标准基于孟德尔随机化的三个主要假设，共有22个SNP进入孟德尔随机化分析。使用IVW方法进行的孟德尔随机化因果关联效应分析结果显示，MPO-DNA复合物水平每增加一个标准差，脓毒症风险增加约18%[比值比（OR）=1.18，95%置信区间（95%CI）为1.07-1.29，P<0.001]，脓毒症28天死亡率风险增加约51%（OR=1.51，95%CI为1.27-1.81，P<0.001），因脓毒症需要重症监护的发生风险增加约38%（OR=1.38，95%CI为1.12-1.70，P=0.002），因脓毒症需要重症监护的28天死亡率风险增加约125%（OR=2.25，95%CI为1.21-4.18，P=0.01）。MR Egger回归截距检验表明纳入的SNP不存在水平多效性，MR-PRESSO检验未发现异常值。敏感性分析表明孟德尔随机化结果具有稳健性。
孟德尔随机化分析表明，NET升高会增加脓毒症发病、进展和死亡的风险。
