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Article Navigation >  CHINESE JOURNAL OF BURNS AND WOUNDS  >  > Accepted Manuscript
Dai Zhanzhan, Zhu Qin, Tong Xirui, et al. Two-sample Mendelian randomization analysis of the causal relationship between inhalation injury and circulating inflammatory proteins in humans[J]. Chin J Burns Wounds. Doi: 10.3760/cma.j.cn501225-20240429-00155
Citation: Dai Zhanzhan, Zhu Qin, Tong Xirui, et al. Two-sample Mendelian randomization analysis of the causal relationship between inhalation injury and circulating inflammatory proteins in humans[J]. Chin J Burns Wounds. Doi: 10.3760/cma.j.cn501225-20240429-00155
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Two-sample Mendelian randomization analysis of the causal relationship between inhalation injury and circulating inflammatory proteins in humans

doi: 10.3760/cma.j.cn501225-20240429-00155

  • Burn Institute of PLA, Department of Burn Surgery, the First Affiliated Hospital of Naval Medical University, Research Unit of Key Techniques for Treatment of Burns and Combined Burns and Trauma Injury, Chinese Academy of Medical Sciences, Shanghai 200433, ChinaDai Zhanzhan is now working at Naval Military Medical University Guard Training Base, Shanghai200433, China

Funds:

Shanghai Science and Technology Innovation Action Plan 22Y11900200

Youth Science Fund Program of National Natural Science Foundation of China 81701899

Shanghai "Rising Stars of Medical Talents" Youth Development Program SHWSRS 2023-62

The Deep Blue Project of Naval Medical University 2021-28

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  • Corresponding author: Fang He, Email: fanghe_2005@163.com
  • Received Date: 2024-04-29
    Available Online: 2024-10-28
    Abstract
  •   Objective  To explore the causal relationship between inhalation injury and circulating inflammatory proteins in humans.  Methods  This research was based on two-sample Mendelian randomization (MR) analysis. With inhalation injury as the exposure factor and circulating inflammatory proteins as the result, data on inhalation injury (216 993 samples) and 91 circulating inflammatory proteins (14 824 samples) were obtained from the genome-wide association study database, and analysis was conducted by two-sample MR analysis methods. Independent single nucleotide polymorphisms (SNPs) significantly associated with inhalation injury were identified as the instrumental variables using the method of linkage disequilibrium analysis. The inverse variance weighted (IVW) method was mainly used for analysis of the causal relationship between inhalation injury and 91 circulating inflammatory proteins, and further verification was carried out using the weighted median method, weighted pattern method, MR-Egger method, and simple pattern method. Based on the IVW method analysis results, SNPs of inhalation injury conformed to the hypothesis were subjected to Cochran's Q test for heterogeneity assessment, the MR-Egger regression test and the MR-PRESSO outlier test for assessment of horizontal pleiotropy, and the leave-one-out analysis for reliability assessment.  Results  Six SNPs with a significant threshold (P<5×10-5) were identified as representative instrumental variables of inhalation injury, with F values greater than 10, indicating strong correlated instrumental variables. Based on the 6 inhalation injury SNPs, the IVW method analysis revealed a significant causal relationship between inhalation injury and interleukin-20 (IL-20), IL-20 receptor subunit alpha (IL-20RA), IL-5, and tumor necrosis factor receptor superfamily member 9 (TNFRSF9), with odds ratios of 1.01, 1.01, 1.02, and 1.01, respectively, and 95% confidence intervals of 1.00-1.02, 1.00-1.03, 1.01-1.03, and 1.00-1.03, respectively, P<0.05. Results obtained via verification through the weighted median method and MR-Egger method confirmed that the causal relationships between inhalation injury and IL-5 (with odds ratios of 1.02 and 1.03 respectively, confidence intervals of 1.00-1.04 and 1.01-1.04, respectively, P<0.05) as well as TNFRSF9 (with odds ratios of 1.02 and 1.03, respectively, confidence intervals of 1.00-1.04 and 1.01-1.04, respectively, P<0.05) were statistically significant. Conversely, results obtained via verification through the weighted pattern method and simple pattern method indicated that the causal relationships between inhalation injury and IL-20, IL-20RA, IL-5, and TNFRSF9 were not statistically significant (all P values >0.05), thus reinforcing reliance on IVW method outcomes was warranted in this context. Based on the IVW method analysis results, the Cochran's Q test demonstrated no existence of significant heterogeneity among the 6 inhalation injury SNPs that had significant causal relationships with IL-20, IL-20RA, IL-5, and TNFRSF9 (with Q values of 2.67, 5.00, 5.17, and 5.29, respectively, P>0.05); assessments using the MR-Egger regression test along with MR-PRESSO outlier test confirmed that there was no significant horizontal pleiotropy among the 6 inhalation injury SNPs that had significant causal relationships with IL-20, IL-20RA, IL-5, and TNFRSF9 (with intercepts of 0.01, <0.01, -0.02, and -0.03, respectively, RSSobs values of 3.33, 9.00, 7.88, and 7.26, respectively, P>0.05); the leave-one-out analysis showed that the significant causal relationship between inhalation injury and IL-20, IL-20RA, IL-5, and TNFRSF9 was stable and reliable after removing the 6 inhalation injury SNPs one by one.  Conclusions  Two-sample MR analysis elucidates significant causal relationships between inhalation injury and four circulating inflammatory proteins, namely IL-20, IL-20RA, IL-5, and TNFRSF9, suggesting an upward trend in the generation of the above four circulating inflammatory proteins following instances of inhalation injury.

     

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