Abstract：
OBJECTIVE: To investigate the causal relationship between neutrophil extracellular trap (NET) and sepsis based on Mendelian randomization analysis.
METHODS: 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.
RESULTS: 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.
CONCLUSIONS: Rising NET can increase the risk of sepsis onset, progression and death as derived from Mendelian randomization analysis.
METHODS: 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.
RESULTS: 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.
CONCLUSIONS: Rising NET can increase the risk of sepsis onset, progression and death as derived from Mendelian randomization analysis.
摘要：
目的：基于孟德尔随机分析，探讨中性粒细胞胞外诱捕网（NET）与脓毒症的因果关系。
方法：基于Donkel等人的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。选择鹿特丹研究（RS）和用于从英国生物库识别败血症的GWAS数据集来筛选与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），使用MPO-DNA复合物作为暴露因子。MPO-DNA复合物与脓毒症发生风险之间的潜在因果关系，败血症28天死亡,由于败血症需要重症监护,使用两个样本分析了需要重症监护的败血症导致的28天死亡，单因素孟德尔随机化分析方差分析(IVW)的主要分析方法。使用MREgger回归截距测试评估潜在的多效性。使用“留一”检验进行敏感性分析。
结果：GWAS数据来自欧洲男女人口，筛选标准基于孟德尔随机化的三个主要假设，导致22个SNP进入孟德尔随机分析。使用IVW方法的孟德尔随机化因果关联效应分析结果表明，对于MPO-DNA复合物水平的每一个标准偏差增加，败血症的风险增加约18％[比值比（OR）=1.18，95％置信区间（95CI）为1.07-1.29，P<0.001]，脓毒症28天死亡风险增加约51%(OR=1.51,95CI为1.27-1.81,P<0.001),因败血症而需要重症监护的风险增加约38％（OR=1.38，95CI为1.12-1.70，P=0.002），需要重症监护的脓毒症28日死亡风险增加约125%(OR=2.25,95CI为1.21~4.18,P=0.01).MREgger回归截距测试表明，所包含的SNP中没有水平多效性，MR-PRESSO测试没有发现异常值。敏感性分析表明，孟德尔随机化的结果是稳健的。
结论：升高的网可以增加脓毒症发病的风险，从孟德尔随机分析得出的进展和死亡。
方法：基于Donkel等人的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。选择鹿特丹研究（RS）和用于从英国生物库识别败血症的GWAS数据集来筛选与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），使用MPO-DNA复合物作为暴露因子。MPO-DNA复合物与脓毒症发生风险之间的潜在因果关系，败血症28天死亡,由于败血症需要重症监护,使用两个样本分析了需要重症监护的败血症导致的28天死亡，单因素孟德尔随机化分析方差分析(IVW)的主要分析方法。使用MREgger回归截距测试评估潜在的多效性。使用“留一”检验进行敏感性分析。
结果：GWAS数据来自欧洲男女人口，筛选标准基于孟德尔随机化的三个主要假设，导致22个SNP进入孟德尔随机分析。使用IVW方法的孟德尔随机化因果关联效应分析结果表明，对于MPO-DNA复合物水平的每一个标准偏差增加，败血症的风险增加约18％[比值比（OR）=1.18，95％置信区间（95CI）为1.07-1.29，P<0.001]，脓毒症28天死亡风险增加约51%(OR=1.51,95CI为1.27-1.81,P<0.001),因败血症而需要重症监护的风险增加约38％（OR=1.38，95CI为1.12-1.70，P=0.002），需要重症监护的脓毒症28日死亡风险增加约125%(OR=2.25,95CI为1.21~4.18,P=0.01).MREgger回归截距测试表明，所包含的SNP中没有水平多效性，MR-PRESSO测试没有发现异常值。敏感性分析表明，孟德尔随机化的结果是稳健的。
结论：升高的网可以增加脓毒症发病的风险，从孟德尔随机分析得出的进展和死亡。
