Dermatology Center, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
Department of Dermatology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
Front Immunol. 2024 Jul 11;15:1367958. doi: 10.3389/fimmu.2024.1367958. eCollection 2024.
Numerous observational studies have reported associations between circulating cytokines and atopic dermatitis (AD); however, the causal relationships between them remain unclear. To explore the causal correlations and direction of causal effects between AD and levels of 91 circulating cytokines.
Two-sample Mendelian randomization (MR) analyses were conducted to examine the causal relationships between 91 circulating cytokines and AD using summary statistics from genome-wide association studies (GWAS). Reverse MR analyses were performed to investigate reverse causation. Pleiotropy and heterogeneity tests were conducted to assess the robustness of the findings. Additional transcriptome database and clinical peripheral blood mononuclear cells (PBMCs) samples were utilized to validate the results of MR analyses.
Levels of interleukin (IL)-13, IL-18 Receptor 1, Tumor necrosis factor ligand superfamily member 14 (TNFSF14), TNF-related activation-induced cytokine (TRANCE), C-X-C motif chemokine (CXCL)11, IL-33, TNF-beta and CD5 were suggestively associated with the risk of AD (odds ratio, OR: 1.202, 95% CI: 1.0181.422, = 0.030; OR: 1.029, 95% CI: 1.029-1.157, = 0.004; OR: 1.159, 95% CI: 1.018-1.320, = 0.026; OR: 1.111, 95% CI: 1.016-1.214, = 0.020; OR: 0.878, 95% CI: 0.783-0.984, = 0.025; OR: 0.809, 95% CI: 0.661-0.991, = 0.041; OR: 0.945, 95% CI: 0.896-0.997, = 0.038; OR: 0.764, 95% CI: 0.652-0.895, = 8.26e-04). In addition, levels of cytokines including Axin-1, CXCL5, CXCL10, Oncostatin-M (OSM), Sulfotransferase 1A1 (SULT1A1) and TNFSF14 were suggested to be consequences of AD (Beta: -0.080, = 0.016; Beta: -0.062, = 0.036; Beta: -0.066, = 0.049; Beta: -0.073, = 0.013; Beta: -0.089, = 0.008; Beta: -0.079, = 0.031). IL-13, IL-18R1, TNFSF14, and TRANCE were upregulated in both lesional skin biopsies and PBMCs from AD patients.
The study indicates that several cytokines, including IL-13, IL-18R1, TNFSF14, TRANCE, CXCL11, IL-33, TNF-beta, and CD5, are upstream of AD development, whereas a few circulating cytokines are potentially downstream in the development of AD.
许多观察性研究报告了循环细胞因子与特应性皮炎（AD）之间的关联；然而，它们之间的因果关系仍不清楚。本研究旨在探索 AD 与 91 种循环细胞因子之间的因果关联及其因果效应的方向。
采用全基因组关联研究（GWAS）的汇总统计数据，通过两样本孟德尔随机化（MR）分析来研究 91 种循环细胞因子与 AD 之间的因果关系。进行反向 MR 分析以研究反向因果关系。进行了多效性和异质性检验，以评估研究结果的稳健性。还利用了额外的转录组数据库和临床外周血单核细胞（PBMC）样本来验证 MR 分析的结果。
白细胞介素（IL）-13、IL-18 受体 1、肿瘤坏死因子配体超家族成员 14（TNFSF14）、TNF 相关激活诱导细胞因子（TRANCE）、C-X-C 基序趋化因子（CXCL）11、IL-33、TNF-β和 CD5 的水平与 AD 发病风险呈显著相关（比值比，OR：1.202，95%置信区间：1.018-1.422， = 0.030；OR：1.029，95%置信区间：1.029-1.157， = 0.004；OR：1.159，95%置信区间：1.018-1.320， = 0.026；OR：1.111，95%置信区间：1.016-1.214， = 0.020；OR：0.878，95%置信区间：0.783-0.984， = 0.025；OR：0.809，95%置信区间：0.661-0.991， = 0.041；OR：0.945，95%置信区间：0.896-0.997， = 0.038；OR：0.764，95%置信区间：0.652-0.895， = 8.26e-04）。此外，细胞因子 Axin-1、CXCL5、CXCL10、Oncostatin-M（OSM）、Sulfotransferase 1A1（SULT1A1）和 TNFSF14 的水平也被认为是 AD 的结果（Beta：-0.080， = 0.016；Beta：-0.062， = 0.036；Beta：-0.066， = 0.049；Beta：-0.073， = 0.013；Beta：-0.089， = 0.008；Beta：-0.079， = 0.031）。AD 患者皮损活检组织和 PBMC 中均存在 IL-13、IL-18R1、TNFSF14 和 TRANCE 的上调。
本研究表明，几种细胞因子，包括 IL-13、IL-18R1、TNFSF14、TRANCE、CXCL11、IL-33、TNF-β和 CD5，是 AD 发展的上游因素，而少数循环细胞因子可能是 AD 发展的下游因素。
