Shantou University, Guangdong Province, 515000, China.
Liupanshui Maternity and Child Health Care Hospital, Guizhou Province, 553000, China.
Arch Dermatol Res. 2024 Aug 21;316(8):551. doi: 10.1007/s00403-024-03303-7.
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.
增生性瘢痕（HS）是由烧伤或创伤引起的，导致美观和功能问题。然而，观察性研究已经将炎症细胞因子与 HS 联系起来，但涉及的因果途径尚不清楚。我们旨在确定循环炎症细胞因子如何导致 HS 形成。两样本 Mendelian 随机化（MR）用于确定与欧洲裔 766 名患者和 207482 名对照的肥厚性瘢痕相关的遗传变异，该研究纳入了一项全面的、公开的全基因组关联研究（GWAS）。此外，还从一项涉及 14824 名健康参与者的 GWAS 汇总数据中提取了 91 种血浆蛋白的数据。主要使用逆方差加权（IVW）方法研究暴露与结局之间的因果关系。此外，还同时使用 MR-Egger 和加权中位数方法进行了一系列敏感性分析，以增强结论的稳健性。最后，进行了反向 MR 分析，以评估在我们的研究中鉴定的细胞因子与肥厚性瘢痕之间反向因果关系的可能性。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=0.32-0.82，p=0.01）与肥厚性瘢痕风险呈负相关，而 CUB 结构域包含蛋白 1（CDCP1）水平（OR=0.59，95%CI=0.41-0.85，p=0.01）和胶质细胞系衍生神经营养因子（GDNF）水平（OR=1.42，95%CI=1.03-1.96，p=0.01）和程序性细胞死亡配体 1（PD-L1）水平（OR=1.47，95%CI=1.92-2.11，p=0.04）与肥厚性瘢痕风险呈正相关。这些关联在敏感性分析中是相似的。根据我们的 MR 发现，OPG 和 LIF 对肥厚性瘢痕有保护作用，而 CDCP1、GDNF 和 PD-L1 对肥厚性瘢痕有增加风险的作用。我们的研究增加了特定炎症生物标志物途径在肥厚性瘢痕中的作用的现有知识。需要进一步验证以评估这些细胞因子作为肥厚性瘢痕预防和治疗的药理学或生活方式靶点的潜力。
