【摘要】 目的：瘢痕疙瘩是一种以异常纤维化和高复发率为特征的皮肤纤维增生性疾病，其发生和发展与炎症介质密切相关。然而，现有流行病学研究受限于混杂因素和反向因果干扰，难以明确二者的因果关系。因此本研究采用孟德尔随机化(Mendelian randomization,MR)分析研究循环细胞因子与瘢痕疙瘩的因果关系。方法：从全基因组关联研究(genome-wide association study,GWAS)数据中提取与瘢痕疙瘩(结局)显著相关的循环细胞因子(暴露)单核苷酸多态性(single nucleotide polymorphisms,SNPs)，筛选合适的SNPs作为工具变量(instrumental variables,IVs)。暴露数据来自包含8 293名芬兰人的循环细胞因子GWAS汇总数据，结局数据来自英国生物样本库的瘢痕疙瘩GWAS数据。采用逆方差加权法(inverse-variance weighted,IVW)作为主要分析方法，评估循环细胞因子对瘢痕疙瘩的因果效应。同时，采用加权中位数法(weighted median,WME)、MR-Egger回归法、加权模型、简单模型进行敏感性分析。采用MR-Egger回归法、MR多效性残差和与异质性检验(MR pleiotropy residual sum and outlier,MR-PRESSO)法进一步评估可能的水平基因多效性。使用Cochran’s Q检验评估SNP的异质性。使用留一法评估结果的稳健性和一致性。此外，以瘢痕疙瘩为暴露，循环细胞因子为结局，进行反向MR分析，以排除反向因果关联。结果：IVW分析结果显示：2种细胞因子与瘢痕疙瘩存在正向因果关联，分别为巨噬细胞迁移抑制因子(macrophage migration inhibitory factor,MIF)[比值比(odds ratio,OR)=2.081,95%置信区间(confidence interval,CI) 1.219～3.552,P=0.007]和单核细胞趋化蛋白-1(monocyte chemoattractant protein-1,MCP-1)(OR=1.673,95%CI 1.036～2.701,P=0.035)，而干细胞因子(stem cell factor,SCF)与瘢痕疙瘩存在负向因果关联(OR=0.518,95%CI 0.269～0.998,P=0.049)。WME、MR-Egger回归法等的结果与IVW分析结果一致。MR-Egger回归法和MR-PRESSO法的结果显示不存在水平基因多效性(P>0.05)。Cochran’s Q检验结果显示：除白细胞介素-6的异质性检验具有统计学意义外(P=0.014)，其他细胞因子不存在异质性。留一法分析结果进一步证实了循环细胞因子的因果关联。反向MR分析的IVW分析结果显示：瘢痕疙瘩仅与β-神经生长因子(beta-nerve growth factor,β-NGF)存在因果关联(OR=1.048,95%CI 1.002～1.095,P=0.039)。Cochran’s Q检验结果显示：除白细胞介素-5的异质性检验具有统计学意义(P=0.001)，其他细胞因子不存在异质性。MR-Egger回归法和MR-PRESSO法的结果显示不存在水平基因多效性(P>0.05)。结论：MIF和MCP-1与瘢痕疙瘩存在正向因果关联，而SCF与瘢痕疙瘩存在负向因果关联。本研究炎症细胞因子参与瘢痕疙瘩的发病机制提供了新的证据，并为开发治疗瘢痕疙瘩的新靶点提供了线索。更多还原

【Abstract】 Objective: Keloids are fibrotic skin disorders characterized by excessive collagen deposition and a high recurrence rate, closely associated with inflammatory mediators. However, existing epidemiological studies are limited by confounding factors and reverse causality, making it difficult to establish causation. This study aims to investigate the causal relationship between circulating cytokines and keloids using Mendelian randomization analysis.Methods: Significant single nucleotide polymorphisms(SNPs) associated with circulating cytokines(exposures) and keloids(outcomes) were extracted from genome-wide association study(GWAS) summary datasets. Eligible SNPs were selected as instrumental variables(IVs). Exposure data were derived from a cytokine GWAS including 8 293 Finnish participants, and outcome data from a keloid GWAS based on the UK Biobank. The inverse-variance weighted(IVW) method served as the primary analytical approach to estimate causal effects, supplemented by weighted median(WME), MR-Egger regression, and other sensitivity analyses. Horizontal pleiotropy was assessed using MR-Egger regression and the MR pleiotropy residual sum and outlier(MR-PRESSO) test, while Cochran’ s Q test evaluated heterogeneity. Leave-one-out analysis was used to verify robustness and consistency. A reverse MR analysis was also conducted, with keloid as the exposure and cytokines as outcomes, to rule out reverse causation.Results: IVW analysis identified significant positive causal associations between two cytokines and keloids-macrophage migration inhibitory factor(MIF) [odds ratio(OR) =2.081, 95% confidence interval(CI) 1.219 to 3.552, P=0.007] and monocyte chemoattractant protein-1(MCP-1)(OR=1.673, 95% CI 1.036 to 2.701, P=0.035). Conversely, stem cell factor(SCF) showed a negative causal relationship with keloids(OR=0.518, 95% CI 0.269 to 0.998, P=0.049). Results from the MR-Egger and weighted median analyses were consistent with IVW findings. No evidence of horizontal pleiotropy was observed(P>0.05). Except for interleukin-6(P=0.014), no heterogeneity was detected in other cytokines. Leave-one-out analysis further confirmed the robustness of the causal associations. In reverse MR analysis, keloids were causally related only to β-nerve growth factor(beta-NGF)(OR=1.048, 95% CI 1.002 to 1.095, P=0.039), with no heterogeneity or pleiotropy detected in most cytokines(P>0.05).Conclusion: MIF and MCP-1 exhibit positive causal associations with keloid formation, while SCF shows a negative causal relationship. These findings provide new evidence for the causal involvement of inflammatory cytokines in keloid pathogenesis and offer potential molecular targets for developing novel keloid therapies.更多还原