肥厚性疤痕 (HS) 由烧伤或创伤引起，导致美观和功能问题。然而，观察性研究已将炎症细胞因子与热射病联系起来，但所涉及的因果途径尚不清楚。我们的目的是确定循环炎症细胞因子如何促进 HS 形成。在一项全面、公开的全基因组关联研究 (GWAS) 中，使用两个样本孟德尔随机化 (MR) 来识别与肥厚性疤痕相关的遗传变异，该研究涉及 766 名欧洲血统患者和 207,482 名对照。此外，91 种血浆蛋白的数据取自 GWAS 总结，涉及 14,824 名健康参与者。主要使用逆方差加权（IVW）方法研究暴露与结果之间的因果关系。此外，同时采用了一系列敏感性分析，包括 MR-Egger 和加权中位数方法，以加强结论性研究结果的稳健性。最后，进行反向 MR 分析，以评估肥厚性疤痕与我们研究中确定的细胞因子之间反向因果关系的合理性。在炎症细胞因子中，有证据表明骨保护素（OPG）水平（OR = 0.59，95% CI = 0.41 ∼ 0.85，p = 0.01）和白血病抑制因子（LIF）水平（OR = 0.51，95% CI）呈负相关。 = 0.32 ∼ 0.82，p = 0.01）与增生性疤痕风险名义上负相关，而CUB结构域含蛋白1（CDCP1）水平（OR = 0.59，95％CI = 0.41 ∼ 0.85，p = 0.01）神经胶质细胞细胞系源性神经营养因子（GDNF）水平（OR = 1.42，95% CI = 1.03 ∼ 1.96，p = 0.01）和程序性细胞死亡1配体1（PD-L1）水平（OR = 1.47，95% CI = 1.92 ∼ 2.11，p = 0.04）显示与增生性疤痕风险呈正相关。这些关联在敏感性分析中是相似的。根据我们的 MR 研究结果，OPG 和 LIF 对增生性疤痕具有保护作用，而 CDCP1、GDNF 和 PD-L1 对肥厚性疤痕具有增加风险的作用。我们的研究增加了目前关于特定炎症生物标志物途径在肥厚性疤痕中的作用的知识。需要进一步验证来评估这些细胞因子作为预防和治疗肥厚性疤痕的药理学或生活方式目标的潜力。© 2024。作者获得 Springer-Verlag GmbH 德国（Springer Nature 旗下公司）的独家许可。

Hypertrophic scar (HS) results from burns or trauma, causing aesthetic and functional issues. However, observational studies have linked inflammatory cytokines to HS, but the causal pathways involved are unclear. We aimed to determine how circulating inflammatory cytokines contribute to HS formation. Two-sample Mendelian randomization (MR) was used to identify genetic variants associated with hypertrophic scar in a comprehensive, publicly available genome-wide association study (GWAS) involving 766 patients and 207,482 controls of European descent. Additionally, data on 91 plasma proteins were drawn from a GWAS summary involving 14,824 healthy participants. Causal relationships between exposures and outcomes were investigated primarily using the inverse variance weighted (IVW) method. Furthermore, a suite of sensitivity analyses, including MR‒Egger and weighted median approaches, were concurrently employed to fortify the robustness of the conclusive findings. Finally, reverse MR analysis was conducted to evaluate the plausibility of reverse causation between hypertrophic scar and the cytokines identified in our study. In inflammatory cytokines, there was evidence of inverse associations of osteoprotegerin(OPG) levels(OR = 0.59, 95% CI = 0.41 ∼ 0.85, p = 0.01), and leukemia inhibitory factor(LIF) levels(OR = 0.51, 95% CI = 0.32 ∼ 0.82, p = 0.01) are a nominally negative association with hypertrophic scar risk, while CUB domain-domain-containing protein 1(CDCP1) level(OR = 0.59, 95% CI = 0.41 ∼ 0.85, p = 0.01) glial cell line-derived neurotrophic factor(GDNF) levels(OR = 1.42, 95% CI = 1.03 ∼ 1.96, p = 0.01) and programmed cell death 1 ligand 1(PD-L1) levels(OR = 1.47, 95% CI = 1.92 ∼ 2.11, p = 0.04) showed a positive association with hypertrophic scar risk. These associations were similar in the sensitivity analyses. According to our MR findings, OPG and LIF have a protective effect on hypertrophic scar, while CDCP1, GDNF, and PD-L1 have a risk-increasing effect on Hypertrophic scar. Our study adds to the current knowledge on the role of specific inflammatory biomarker pathways in hypertrophic scar. Further validation is needed to assess the potential of these cytokines as pharmacological or lifestyle targets for hypertrophic scar prevention and treatment.© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.