Background Adult asthma is phenotypically heterogeneous with unclear aetiology. We aimed to evaluate the potential contribution of environmental exposure and its ensuing response to asthma and its heterogeneity. Methods Environmental risk was evaluated by assessing the records of National Health Insurance Research Database (NHIRD) and residence-based air pollution (particulate matter with diameter less than 2.5 micrometers (PM2.5) and PM2.5-bound polycyclic aromatic hydrocarbons (PAHs)), integrating biomonitoring analysis of environmental pollutants, inflammatory markers and sphingolipid metabolites in case–control populations with mass spectrometry and ELISA. Phenotypic clustering was evaluated by t-distributed stochastic neighbor embedding (t-SNE) integrating 18 clinical and demographic variables. Findings In the NHIRD dataset, modest increase in the relative risk with time-lag effect for emergency (N=209 837) and outpatient visits (N=638 538) was observed with increasing levels of PM2.5 and PAHs. Biomonitoring analysis revealed a panel of metals and organic pollutants, particularly metal Ni and PAH, posing a significant risk for current asthma (ORs=1.28–3.48) and its severity, correlating with the level of oxidative stress markers, notably Nε-(hexanoyl)-lysine (r=0.108–0.311, p<0.05), but not with the accumulated levels of PM2.5 exposure. Further, levels of circulating sphingosine-1-phosphate and ceramide-1-phosphate were found to discriminate asthma (p<0.001 and p<0.05, respectively), correlating with the levels of PAH (r=0.196, p<0.01) and metal exposure (r=0.202–0.323, p<0.05), respectively, and both correlating with circulating inflammatory markers (r=0.186–0.427, p<0.01). Analysis of six phenotypic clusters and those cases with comorbid type 2 diabetes mellitus (T2DM) revealed cluster-selective environmental risks and biosignatures. Interpretation These results suggest the potential contribution of environmental factors from multiple sources, their ensuing oxidative stress and sphingolipid remodeling to adult asthma and its phenotypic heterogeneity. All data relevant to the study are included in the article or uploaded as online supplemental information.

中文翻译：

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成人哮喘及其表型群的环境风险和鞘脂特征：一项多中心研究

背景 成人哮喘具有不明病因的表型异质性。我们的目的是评估环境暴露的潜在贡献及其对哮喘及其异质性的后续反应。方法 通过评估国家健康保险研究数据库 (NHIRD) 和居住地空气污染（直径小于 2.5 微米的颗粒物 (PM2.5) 和 PM2.5 结合的多环芳烃 (PAHs)）的记录来评估环境风险)，将环境污染物、炎症标志物和鞘脂代谢物的生物监测分析与质谱和 ELISA 结合在病例对照人群中。通过整合 18 个临床和人口统计变量的 t 分布随机邻域嵌入 (t-SNE) 评估表型聚类。在 NHIRD 数据集中的发现，随着 PM2.5 和 PAH 水平的升高，急诊 (N=209 837) 和门诊就诊 (N=638 538) 的相对风险随时间滞后效应适度增加。生物监测分析显示，一组金属和有机污染物，尤其是金属镍和多环芳烃，对当前哮喘 (ORs=1.28–3.48) 及其严重程度构成重大风险，与氧化应激标志物水平相关，尤其是 Nε-（己酰基） -赖氨酸 (r=0.108–0.311, p<0.05)，但与 PM2.5 暴露的累积水平无关。此外，发现循环中的 1-磷酸鞘氨醇和 1-磷酸神经酰胺水平可区分哮喘（分别为 p<0.001 和 p<0.05），与 PAH（r=0.196，p<0.01）和金属水平相关分别暴露 (r=0.202–0.323, p<0.05), 两者都与循环炎症标志物相关 (r=0.186–0.427, p<0.01)。对六个表型簇和合并 2 型糖尿病 (T2DM) 的病例的分析揭示了簇选择性环境风险和生物印记。解释 这些结果表明来自多种来源的环境因素、它们随之而来的氧化应激和鞘脂重塑对成人哮喘及其表型异质性的潜在贡献。与研究相关的所有数据都包含在文章中或作为在线补充信息上传。解释 这些结果表明来自多种来源的环境因素、它们随之而来的氧化应激和鞘脂重塑对成人哮喘及其表型异质性的潜在贡献。与研究相关的所有数据都包含在文章中或作为在线补充信息上传。解释 这些结果表明来自多种来源的环境因素、它们随之而来的氧化应激和鞘脂重塑对成人哮喘及其表型异质性的潜在贡献。与研究相关的所有数据都包含在文章中或作为在线补充信息上传。