Mediated Mendelian randomization study on the causal relationship between human circulating inflammatory proteins and pressure injury mediated by human blood metabolites
10.3760/cma.j.cn501225-20250331-00152
- VernacularTitle:人血液代谢物介导的人循环炎症蛋白与压力性损伤之间因果关系的中介孟德尔随机化研究
- Author:
Tao CHEN
1
;
Shaoying GAO
1
;
Zairong WEI
1
Author Information
1. 遵义医科大学附属医院烧伤整形外科，遵义 563003
- Publication Type:Journal Article
- Keywords:
Mendelian randomization analysis;
Databases, genetic;
Causality;
Pressure injury;
Circulating inflammatory proteins;
Metabolite
- From:
Chinese Journal of Burns
2025;41(7):635-644
- CountryChina
- Language:Chinese
-
Abstract:
Objective:To explore the causal relationship between human circulating inflammatory proteins and pressure injury (PI) mediated by human blood metabolites.Methods:This study employed a method of analysis based on mediated Mendelian randomization (MR). Genome-wide association study data of 91 human circulating inflammatory proteins (14 824 samples), 1 400 human blood metabolites (8 299 samples), and PI (467 794 samples) were retrieved. A significance threshold was established and single nucleotide polymorphisms (SNPs) were used as instrumental variables with the influence of weak instrumental variables excluded. Forward two-sample MR (TSMR) was employed to analyze the causal relationship between circulating inflammatory proteins and PI. The inverse variance weighted (IVW) method served as the primary approach, and the results were validated using the weighted median method, MR-Egger regression, weighted mode method, and simple mode method (the specific analytical methods were the same below). For the SNPs of selected circulating inflammatory proteins, sensitivity analysis was employed, including heterogeneity which was evaluated by the Cochran Q test, horizontal pleiotropy which was evaluated by the MR-Egger intercept test and MR-PRESSO outlier test, and reliability which was evaluated via leave-one-out analysis. Based on reverse TSMR analysis, the IVW method, MR-Egger regression, weighted median method, simple mode method, and weighted mode method were employed to evaluate whether a reverse causal relationship exists between PI and the selected circulating inflammatory proteins. Forward TSMR was employed to analyze the causal relationship between selected circulating inflammatory proteins and 1 400 blood metabolites and to select the blood metabolites. For the SNPs of selected circulating inflammatory proteins, sensitivity analysis was employed as before. Forward TSMR was employed to analyze the causal relationship between selected blood metabolites and PI. For the SNPs of selected blood metabolites, sensitivity analysis was employed as before (except for the leave-one-out analysis). Finally, the mediation effect values and mediation effect ratios of selected blood metabolites in the mediation effect between selected circulating inflammatory proteins and PI were calculated. Results:Five circulating inflammatory proteins and 59 blood metabolites were identified as meeting the exposure factor criteria, with the number of SNPs reaching the significance threshold ranging from 16 to 1 484. All the SNPs were confirmed as strong instrumental variables. The IVW method revealed significant causal relationships between interleukin-33 (IL-33), CUB domain-containing protein 1, IL-5, stem cell factor, and tumor necrosis factor and PI (with odds ratios of 1.29, 1.20, 1.25, 1.16, and 1.23, respectively, 95% confidence intervals of 1.07-1.55, 1.05-1.36, 1.04-1.51, 1.00-1.34, and 1.03-1.47, respectively, P<0.05). The weighted median method confirmed significant causal relationships between IL-33 and IL-5 and PI (with odds ratios of 1.37 and 1.37, respectively, 95% confidence intervals of 1.05-1.79 and 1.04-1.80, respectively, P<0.05). Among these, the most significant causal relationship was observed between IL-33 and PI ( P<0.01). The Cochran Q test indicated no significant heterogeneity in the SNPs of IL-33 which had significant causal relationship with PI ( Q=18.78, P>0.05). The MR-Egger intercept test (with intercept absolute value <0.001, P>0.05) and MR-PRESSO outlier test (with RSSobs value of 20.37, P>0.05) both indicated no significant horizontal pleiotropy in the SNPs of IL-33 which had significant causal relationship with PI. The leave-one-out analysis showed that the significant causal relationship between IL-33 and PI was reliable after removing the SNPs one by one. No significant reverse causal relationships were observed between PI and IL-33 through the IVW method, MR-Egger regression, weighted median method, simple mode method, or weighted mode method (with odds ratios of 1.00, 1.00, 1.00, 1.00, and 1.01, respectively, 95% confidence intervals of 0.98-1.02, 0.96-1.03, 0.97-1.03, 0.93-1.08, and 0.94-1.09, respectively, P>0.05). The IVW method revealed significant causal relationships between IL-33 and 59 blood metabolites (with odds ratios of 0.79-1.20, 95% confidence intervals lower limit range of 0.70-1.07 and upper limit range of 0.89-1.37, P<0.05). The MR-Egger regression and weighted median method confirmed significant causal relationships between IL-33 and 8 and 10 blood metabolites, respectively (with odds ratios of 0.63-1.70 and 0.82-1.21, respectively, 95% confidence intervals lower limit ranges of 0.43-1.29 and 0.70-1.14, respectively, 95% confidence intervals upper limit ranges of 0.94-2.25 and 0.97-1.42, respectively, P values all <0.05). Among these, the most significant causal relationship was observed between blood metabolite X-12798 and IL-33 (with odds ratio of 0.79, 95% confidence interval of 0.70-0.89, P<0.05). The Cochran Q test indicated no significant heterogeneity in the SNPs of IL-33 which had significant causal relationship with blood metabolite X-12798 ( Q=24.94, P>0.05). The MR-Egger intercept test (with intercept absolute value of 0.012, P>0.05) and MR-PRESSO outlier test (with RSSobs value of 27.45, P>0.05) both indicated no significant horizontal pleiotropy in the SNPs of IL-33 which had significant causal relationship with blood metabolite X-12798. The leave-one-out analysis showed that the significant causal relationship between IL-33 and blood metabolite X-12798 was reliable after removing the SNPs one by one. The IVW method revealed significant causal relationship between blood metabolite X-12798 and PI (with odds ratio of 0.92, 95% confidence interval of 0.84-0.99, P<0.05). The MR-Egger regression and weighted median method both confirmed significant causal relationship between blood metabolite X-12798 and PI (with odds ratios of 0.87 and 0.89, respectively, 95% confidence intervals of 0.77-0.98 and 0.80-0.99, respectively, P<0.05). The Cochran Q test indicated no significant heterogeneity in the SNPs of blood metabolite X-12798 which had significant causal relationship with PI ( Q=23.45, P>0.05). The MR-Egger intercept test (with intercept absolute value of 0.015, P>0.05) and MR-PRESSO outlier test (with RSSobs value of 26.01, P>0.05) both indicated no significant horizontal pleiotropy in the SNPs of blood metabolite X-12798 which had significant causal relationship with PI. The mediation effect value was 0.02 and the mediation effect ratio was 8.27%. Conclusions:Significant causal relationships are observed among human circulating inflammatory proteins, blood metabolites, and PI, with the association between circulating inflammatory protein IL-33 and PI being mediated by blood metabolite X-12798.
