School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China.
School of Life Sciences, Beijing University of Chinese Medicine, Beijing, China.
Sci Rep. 2024 Oct 8;14(1):23435. doi: 10.1038/s41598-024-74522-1.
Atopic dermatitis (AD) is a chronic inflammatory skin disease affecting tens of millions of people globally. The causal relationship between metabolites and AD pathology has not yet been formally indicated, and the mediating mechanism by which metabolites affect AD has not yet been explored. This study aimed to determine the genetic relationship between metabolites and AD and to determine the pathways through which amino acid metabolites affect AD. Meta-analysis integrates the results of multiple GWAS analyses using METAL software. Using bidirectional two-sample Mendelian randomization (MR), we analyzed the causal relationships between metabolites and AD. The principal MR test of causal effects was conducted using inverse-variance weighted regression, and we used reverse MR analysis to exclude reverse causality. We also performed the MR-PRESSO test to detect and correct for possible pleiotropic effects, and used the Cochran Q test to assess heterogeneity. Two-step MR was utilized to analyze the mediating factors between amino acid metabolites and the onset of AD. The correlation between mediating factors (inflammatory protein S100A12) and immune cell infiltration was analyzed using the edgeR and GSVA software packages. Using single-cell sequencing data from skin tissues of patients with AD, we studied the regulatory role of the S100A12 gene in immune cells. Multiple drug databases and macromolecular docking were used to search for S100A12-targeting drugs. Bidirectional two-sample MR analyses indicated that twenty-two metabolites and one inflammatory protein (S100A12) were significantly associated with AD pathogenesis. S100A12 is a mediator of amino acid metabolites (N6-methyllysine; N2-acetyl,N6,N6-dimethyllysine and N6,N6-dimethyllysine) that are genetically associated with AD. S100A12 was positively correlated with the infiltration of multiple immune cell types in lesional AD skin. The amino acid metabolites N6-methyllysine; N2-acetyl,N6,N6-dimethyllysine and N6,N6-dimethyllysine influence AD pathogenesis by mediating S100A12 expression.
特应性皮炎（AD）是一种影响全球数千万人的慢性炎症性皮肤病。代谢物与 AD 病理之间的因果关系尚未得到正式证实，代谢物影响 AD 的中介机制也尚未得到探索。本研究旨在确定代谢物与 AD 之间的遗传关系，并确定氨基酸代谢物影响 AD 的途径。荟萃分析使用 METAL 软件整合了多项 GWAS 分析的结果。采用双向二样本 Mendelian 随机化（MR）分析，我们分析了代谢物与 AD 之间的因果关系。采用逆方差加权回归进行主要 MR 因果效应检验，并用反向 MR 分析排除反向因果关系。我们还进行了 MR-PRESSO 检验以检测和纠正可能的多效性效应，并使用 Cochran Q 检验评估异质性。两步 MR 分析用于分析氨基酸代谢物与 AD 发病之间的中介因素。使用 edgeR 和 GSVA 软件包分析了中介因素（炎症蛋白 S100A12）与免疫细胞浸润之间的相关性。使用 AD 患者皮肤组织的单细胞测序数据，我们研究了 S100A12 基因在免疫细胞中的调控作用。使用多种药物数据库和大分子对接搜索 S100A12 靶向药物。双向二样本 MR 分析表明，二十二种代谢物和一种炎症蛋白（S100A12）与 AD 发病机制显著相关。S100A12 是与 AD 遗传相关的氨基酸代谢物（N6-甲基赖氨酸；N2-乙酰基，N6，N6-二甲基赖氨酸和 N6，N6-二甲基赖氨酸）的中介物。S100A12 与病变 AD 皮肤中多种免疫细胞类型的浸润呈正相关。氨基酸代谢物 N6-甲基赖氨酸；N2-乙酰基，N6，N6-二甲基赖氨酸和 N6，N6-二甲基赖氨酸通过介导 S100A12 表达影响 AD 发病机制。
