Mendelian randomization analysis of the causal relationships between human inflammatory proteins and keloids

Li Tao; Zhu Chenchen; Chen Jinyuan; Li Puzhen; Jin Peisheng; Li Xueyang

doi:10.3760/cma.j.cn501225-20240526-00198

Volume 41 Issue 2

Feb. 2025

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Article Navigation > CHINESE JOURNAL OF BURNS AND WOUNDS > 2025 > 41(2): 180-187

Li T,Zhu CC,Chen JY,et al.Mendelian randomization analysis of the causal relationships between human inflammatory proteins and keloids[J].Chin J Burns Wounds,2025,41(2):180-187.DOI: 10.3760/cma.j.cn501225-20240526-00198.

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Mendelian randomization analysis of the causal relationships between human inflammatory proteins and keloids

doi: 10.3760/cma.j.cn501225-20240526-00198

Department of Plastic Surgery, the Affiliated Hospital of Xuzhou Medical University, Xuzhou 221000, China

Funds:

General Program of National Natural Science Foundation of China 82172224

Xuzhou Municipal Health Commission Key Scientific and Technological Project XWKYHT20220136

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Corresponding author: Li Xueyang, Email: xyfylxy@126.com
Received Date: 2024-05-26

Abstract

Abstract

Objective To explore the causal relationships between human inflammatory proteins and keloids. Methods This study was based on Mendelian randomization (MR) analysis. Human inflammatory proteins were considered as the exposure factors, and keloid was considered as the outcome. Data on 91 inflammatory proteins (14 824 samples) and keloids (668 samples) were obtained from the genome-wide association study database. A significance threshold was established to discern single nucleotide polymorphisms (SNPs) significantly associated with inflammatory proteins as instrumental variables with the influence of weak instrumental variables being excluded. For the analysis of a single instrumental variable, the Wald ratio method was used; for the analysis of multiple instrumental variables, the inverse variance weighted (IVW) method was used as the primary method, with the weighted median method, simple mode method, weighted mode method, and MR-Egger method as supplementary methods to employ two-sample MR analysis to analyze the causal relationships between inflammatory proteins and keloids. Using the IVW method, weighted median method, and MR-Egger method to employ multi-sample MR (MVMR) analysis to evaluate the statistically significant inflammatory proteins in the above-mentioned two-sample MR analysis, thus validating their independent causal relationships with keloids. For SNPs of inflammatory proteins conformed to the hypothesis, the Cochran Q test was used to assess heterogeneity, the MR-Egger regression test and MR-PRESSO outlier test were used to evaluate horizontal pleiotropy, and the leave-one-out analysis was performed to assess reliability. Results Seventy-five inflammatory proteins met the exposure factor criteria, with the number of SNPs reaching a significance threshold ranging from 1 to 7 082 (with F values all >10), indicating minimal potential for weak instrumental variable bias in this study. The IVW method analysis revealed significant causal relationships between eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1), CD5, and osteoprotegerin and keloids (with odds ratios of 0.50, 0.61, and 0.71, respectively, 95% confidence intervals of 0.32-0.77, 0.41-0.89, and 0.52-0.97, respectively, P<0.05); the weighted median method confirmed a significant causal relationship between CD5 and keloids (with odds ratio of 0.61, 95% confidence interval of 0.38-0.97, P<0.05); the simple mode method, weighted mode method, and MR-Egger method confirmed no significant causal relationships between CD5 and osteoprotegerin and keloids (P>0.05). The Wald ratio method analysis revealed a significant causal relationship between programmed death-ligand 1 (PD-L1) and keloids (with odds ratio of 1.83, 95% confidence interval of 1.06-3.15, P<0.05). Thus IVW method results were considered as the standard. The IVW method analysis confirmed that 4E-BP1, CD5, osteoprotegerin, and PD-L1 maintained significant causal relationships with keloids (with odds ratios of 0.43, 0.58, 0.70, and 1.95, respectively, 95% confidence intervals of 0.28-0.67, 0.39-0.86, 0.51-0.95, and 1.16-3.27, respectively, P<0.05). The MR-Egger method confirmed significant causal relationships between 4E-BP1 and CD5 and keloids (with odds ratios of 0.41 and 0.58, respectively, 95% confidence intervals of 0.22-0.77 and 0.39-0.88, respectively, P<0.05). The weighted median method confirmed significant causal relationships between 4E-BP1 and PD-L1 and keloids (with odds ratios of 0.46 and 2.06, respectively, 95% confidence intervals of 0.26-0.82 and 1.11-3.81, respectively, P<0.05). The Cochran Q test assessment indicated no significant heterogeneity in the SNPs of CD5 and osteoprotegerin that had significant causal relationships with keloids (P>0.05). The MR-Egger regression test and MR-PRESSO outlier test showed no significant horizontal pleiotropy in the SNPs of CD5 and osteoprotegerin that had significant causal relationships with keloids (P>0.05). The leave-one-out analysis confirmed that the significant causal relationships between CD5 and osteoprotegerin and keloids remained stable after sequentially removing individual SNP. Conclusions Two-sample MR analysis and MVMR analysis confirmed significant causal relationships between 4E-BP1, CD5, and osteoprotegerin and keloids, all of which are protective factors for keloids.
- Keloid,
- Mendelian randomization analysis,
- Databases, genetic,
- Causality,
- Inflammatory proteins

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