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Volume 41 Issue 7
Jul.  2025
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Article Navigation >  CHINESE JOURNAL OF BURNS AND WOUNDS  > 2025  >  41(7): 635-644
Chen Tao, Gao Shaoying, Wei Zairong. Mediated Mendelian randomization study on the causal relationship between human circulating inflammatory proteins and pressure injury mediated by human blood metabolites[J]. CHINESE JOURNAL OF BURNS AND WOUNDS, 2025, 41(7): 635-644. Doi: 10.3760/cma.j.cn501225-20250331-00152
Citation: Chen Tao, Gao Shaoying, Wei Zairong. Mediated Mendelian randomization study on the causal relationship between human circulating inflammatory proteins and pressure injury mediated by human blood metabolites[J]. CHINESE JOURNAL OF BURNS AND WOUNDS, 2025, 41(7): 635-644. Doi: 10.3760/cma.j.cn501225-20250331-00152
shu

Mediated Mendelian randomization study on the causal relationship between human circulating inflammatory proteins and pressure injury mediated by human blood metabolites

doi: 10.3760/cma.j.cn501225-20250331-00152

  • Department of Burns and Plastic Surgery, Affiliated Hospital of Zunyi Medical University, Zunyi 563003, China

Funds:

Regional Science Foundation Project of National Natural Science Foundation of China 82360445

Research Project on Traditional Chinese Medicine and Ethnic Medicine Science and Technology of Guizhou Provincial Administration of Traditional Chinese Medicine QZYY-2024-031

Science and Technology Fund Project of Guizhou Provincial Health Commission gzwkj2024-155

Scientific Research and Talent Training Funds of Kweichow Moutai Hospital mtyk2022-13

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    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.

     

    • (1) From a genetic perspective, mediated Mendelian randomization analysis revealed that human blood metabolite X-12798 played a significant mediating role between human circulating inflammatory proteins and pressure injury.
    (2) The research findings were based on publicly available large-scale genome-wide association study data, which had the advantages of large sample sizes and reduced impact from confounding factors.
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    • References(44)
  • [1]
    沈晓娴, 周增丁, 刘健明, 等. 红外热像仪联合Braden评估表在预防严重烧伤患者1期压力性损伤中的应用研究[J]. 组织工程与重建外科杂志, 2024, 20(3): 322-325. DOI: 10.3969/j.issn.1673-0364.2024.03.008.
    [2]
    Zajac KK, Schubauer K, Simman R. The unavoidable pressure injury/ulcer: a review of skin failure in critically ill patients[J]. J Wound Care, 2024, 33(Suppl 9): S18-22. DOI: 10.12968/jowc.2024.0079.
    [3]
    Gould LJ, Alderden J, Aslam R, et al. WHS guidelines for the treatment of pressure ulcers-2023 update[J]. Wound Repair Regen, 2024, 32(1): 6-33. DOI: 10.1111/wrr.13130.
    [4]
    蒋琪霞, 周济宏, 陈可塑, 等. 中国46所三级医院成年住院患者压力性损伤流行病学特征及Braden量表预测作用研究[J]. 中国全科医学, 2023, 26(18): 2195-2202. DOI: 10.12114/j.issn.1007-9572.2022.0796.
    [5]
    Yang D, Zhang R, Kirkland-Kyhn H. Training and practice of wound ostomy continence nurse specialists in China[J]. Wound Manag Prev, 2023, 69(3): 28-31. DOI: 10.25270/wmp.22083.
    [6]
    Chung ML, Widdel M, Kirchhoff J, et al. Risk factors for pressure ulcers in adult patients: a meta-analysis on sociodemographic factors and the Braden scale[J]. J Clin Nurs, 2023, 32(9/10): 1979-1992. DOI: 10.1111/jocn.16260.
    [7]
    曹丽敏, 黄子慧, 王裕玲, 等. 复方五凤草液负压滴灌治疗Ⅲ-Ⅳ期压力性损伤的疗效及其作用机制[J]. 解放军医学杂志, 2024, 49(4): 396-407. DOI: 10.11855/j.issn.0577-7402.2664.2023.0822.
    [8]
    Emdin CA, Khera AV, Kathiresan S. Mendelian randomization [J]. JAMA, 2017, 318(19): 1925-1926. DOI: 10.1001/jama.2017.17219.
    [9]
    Xia X, Tie X, Hong M, et al. Exploration of the causal relationship and mechanisms between serum albumin and venous thrombosis: a bidirectional mendelian randomization analysis and bioinformatics study[J]. Thromb J, 2025, 23(1): 17. DOI: 10.1186/s12959-025-00700-4.
    [10]
    Chen L, Zhang M, Xiang S, et al. Post-traumatic stress disorder and risk of systemic lupus erythematosus: meta-analysis and Mendelian randomization study[J]. J Psychosom Res, 2025, 190: 112049. DOI: 10.1016/j.jpsychores.2025.112049.
    [11]
    代站站, 朱沁, 佟希睿, 等. 人吸入性损伤与循环炎症蛋白之间因果关系的双样本孟德尔随机化分析[J]. 中华烧伤与创面修复杂志, 2024, 40(11): 1043-1051. DOI: 10.3760/cma.j.cn501225-20240429-00155.
    [12]
    Morán MDC, Porredon C, Gibert C. Insight into the antioxidant activity of ascorbic acid-containing gelatin nanoparticles in simulated chronic wound conditions[J]. Antioxidants (Basel), 2024, 13(3): 299. DOI: 10.3390/antiox13030299.
    [13]
    Mu X, Chen J, Zhu H, et al. Asiaticoside-nitric oxide synergistically accelerate diabetic wound healing by regulating key metabolites and SRC/STAT3 signaling[J/OL]. Burns Trauma, 2025, 13: tkaf009[2025-03-31]. https://pubmed.ncbi.nlm.nih.gov/40066291/. DOI: 10.1093/burnst/tkaf009.
    [14]
    Pan SC, Wu YF, Lin YC, et al. Monocyte chemoattractant protein-1 detection in wound tissue fluids for the assisted diagnosis of wound infection[J]. Surgery, 2024, 176(1): 154-161. DOI: 10.1016/j.surg.2024.03.003.
    [15]
    Kim JY, Shin YK, Seol GH. Incidence and risk factors for pressure injury in hospitalized non-small cell lung cancer patients: a retrospective observational study[J]. J Tissue Viability, 2023, 32(3): 377-382. DOI: 10.1016/j.jtv.2023.05.008.
    [16]
    Cao H, Shi C, Aihemaiti Z, et al. Association between circulating inflammatory proteins and benign prostatic disease: a Mendelian randomization study[J]. Sci Rep, 2024, 14(1): 23667. DOI: 10.1038/s41598-024-74737-2.
    [17]
    Barman PK, Koh TJ. Macrophage dysregulation and impaired skin wound healing in diabetes[J]. Front Cell Dev Biol, 2020, 8: 528. DOI: 10.3389/fcell.2020.00528.
    [18]
    Kwek MSY, Thangaveloo M, Madden LE, et al. Targeting Cx43 to reduce the severity of pressure ulcer progression [J]. Cells, 2023, 12(24): 2856. DOI: 10.3390/cells12242856.
    [19]
    Wilson P, Patton D, O'Connor T, et al. Biomarkers of local inflammation at the skin's surface may predict both pressure and diabetic foot ulcers[J]. J Wound Care, 2024, 33(9): 630-635. DOI: 10.12968/jowc.2024.0127.
    [20]
    Montcusí B, Madrid-Gambin F, Pozo ÓJ, et al. Circulating metabolic markers after surgery identify patients at risk for severe postoperative complications: a prospective cohort study in colorectal cancer[J]. Int J Surg, 2024, 110(3): 1493-1501. DOI: 10.1097/JS9.0000000000000965.
    [21]
    Gou Y, Lv BH, Zhang JF, et al. Identifying early predictive and diagnostic biomarkers and exploring metabolic pathways for sepsis after trauma based on an untargeted metabolomics approach[J]. Sci Rep, 2025, 15(1): 12068. DOI: 10.1038/s41598-025-92631-3.
    [22]
    Birney E. Mendelian randomization[J]. Cold Spring Harb Perspect Med, 2022, 12(4): a041302. DOI: 10.1101/cshperspect.a041302.
    [23]
    吴虹林, 陈咏菲, 李舒婷, 等. 双样本双向孟德尔随机化法分析人免疫细胞与增生性瘢痕之间的因果关系[J]. 中华烧伤与创面修复杂志, 2024, 40(6): 572-578. DOI: 10.3760/cma.j.cn501225-20240203-00046.
    [24]
    Zhao JH, Stacey D, Eriksson N, et al. Genetics of circulating inflammatory proteins identifies drivers of immune-mediated disease risk and therapeutic targets[J]. Nat Immunol, 2023, 24(9): 1540-1551. DOI: 10.1038/s41590-023-01588-w.
    [25]
    Chen Y, Lu T, Pettersson-Kymmer U, et al. Genomic atlas of the plasma metabolome prioritizes metabolites implicated in human diseases[J]. Nat Genet, 2023, 55(1): 44-53. DOI: 10.1038/s41588-022-01270-1.
    [26]
    Wang C, Zhu D, Zhang D, et al. Causal role of immune cells in schizophrenia: Mendelian randomization (MR) study[J]. BMC Psychiatry, 2023, 23(1): 590. DOI: 10.1186/s12888-023-05081-4.
    [27]
    Guo MN, Hao XY, Tian J, et al. Human blood metabolites and lacunar stroke: a Mendelian randomization study[J]. Int J Stroke, 2023, 18(1): 109-116. DOI: 10.1177/17474930221140792.
    [28]
    李涛, 朱晨晨, 陈今源, 等. 人炎症蛋白与瘢痕疙瘩之间因果关系的孟德尔随机化分析[J]. 中华烧伤与创面修复杂志, 2025, 41(2): 180-187. DOI: 10.3760/cma.j.cn501225-20240526-00198.
    [29]
    Gao Y, Cai L, Li D, et al. Extended characterization of IL-33/ST2 as a predictor for wound age determination in skin wound tissue samples of humans and mice[J]. Int J Legal Med, 2023, 137(4): 1287-1299. DOI: 10.1007/s00414-023-03025-x.
    [30]
    Yuan C. IL-33 in autoimmunity; possible therapeutic target [J]. Int Immunopharmacol, 2022, 108: 108887. DOI: 10.1016/j.intimp.2022.108887.
    [31]
    Lei WJ, Zhang F, Lin YK, et al. IL-33/ST2 axis of human amnion fibroblasts participates in inflammatory reactions at parturition[J]. Mol Med, 2023, 29(1): 88. DOI: 10.1186/s10020-023-00668-9.
    [32]
    Gong C, Jin Y, Wang X, et al. Lack of S1PR2 in macrophage ameliorates sepsis-associated lung injury through inducing IL-33-mediated type 2 immunity[J]. Am J Respir Cell Mol Biol, 2024, 70(3): 215-225. DOI: 10.1165/rcmb.2023-0075OC.
    [33]
    Shi P, Sun P, Lou C, et al. Adventitial injection of hyaluronic acid/sodium alginate hydrogel loaded with IL-33 antibody decreases neointimal hyperplasia[J]. J Surg Res, 2025, 305: 107-117. DOI: 10.1016/j.jss.2024.11.017.
    [34]
    Tsuda H, Tominaga SI, Ohtsuki M, et al. Nuclear IL-33 regulates cytokinesis and cell motility in normal human epidermal keratinocytes[J]. J Dermatol Sci, 2022, 105(2): 113-120. DOI: 10.1016/j.jdermsci.2022.01.006.
    [35]
    Jin M, Komine M, Tsuda H, et al. Interleukin-33 deficiency protects the skin from ulcer formation in an ischemia-reperfusion-induced decubitus mouse model[J]. Exp Dermatol, 2024, 33(11): e70014. DOI: 10.1111/exd.70014.
    [36]
    Bonzano L, Borgia F, Casella R, et al. Microbiota and IL-33/31 axis linkage: implications and therapeutic perspectives in atopic dermatitis and psoriasis[J]. Biomolecules, 2023, 13(7): 1100. DOI: 10.3390/biom13071100.
    [37]
    Kobayashi T, Moro K. Tissue-specific diversity of group 2 innate lymphoid cells in the skin[J]. Front Immunol, 2022, 13: 885642. DOI: 10.3389/fimmu.2022.885642.
    [38]
    Chen Y, Ma L, Cheng Z, et al. Senescent fibroblast facilitates re-epithelization and collagen deposition in radiation-induced skin injury through IL-33-mediated macrophage polarization[J]. J Transl Med, 2024, 22(1): 176. DOI: 10.1186/s12967-024-04972-8.
    [39]
    Pinto C, Carrasco-Loncharic T, González-Mienert E, et al. IL-33 induces a switch in intestinal metabolites revealing the tryptophan pathway as a target for inducing allograft survival[J]. Nutrients, 2024, 16(21): 3655. DOI: 10.3390/nu16213655.
    [40]
    Zhong H, Liu S, Zhu J, et al. Elucidating the role of blood metabolites on pancreatic cancer risk using two-sample Mendelian randomization analysis[J]. Int J Cancer, 2024, 154(5): 852-862. DOI: 10.1002/ijc.34771.
    [41]
    王建, 张炎, 程璐, 等. 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[J]. 中华危重病急救医学, 2023, 35(10): 1045-1052. DOI: 10.3760/cma.j.cn121430-20230117-00030.
    [42]
    Cheon SY, Park JH, Ameri AH, et al. IL-33/regulatory T-cell axis suppresses skin fibrosis[J]. J Invest Dermatol, 2022, 142(10): 2668-2676.e4. DOI: 10.1016/j.jid.2022.03.009.
    [43]
    Wang Y, Ding H, Bai R, et al. Exosomes from adipose-derived stem cells accelerate wound healing by increasing the release of IL-33 from macrophages[J]. Stem Cell Res Ther, 2025, 16(1): 80. DOI: 10.1186/s13287-025-04203-x.
    [44]
    Luo CH, Lai AC, Chang YJ. Butyrate inhibits Staphylococcus aureus-aggravated dermal IL-33 expression and skin inflammation through histone deacetylase inhibition[J]. Front Immunol, 2023, 14: 1114699. DOI: 10.3389/fimmu.2023.1114699.
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