Background

There is limited data on the mechanisms of aspirin desensitization in patients with nonsteroidal anti-inflammatory drug (NSAID)-induced urticaria/angioedema (NIUA).

Objectives

We sought to characterize the transcriptomic and metabolomic profiles of patients with NIUA undergoing aspirin desensitization.

Methods

PBMCs and plasma were separated from the blood of patients with NIUA undergoing aspirin desensitization for coronary artery disease and NSAID-tolerant controls. RNA was isolated from PBMCs and subjected to messenger RNA (mRNA)- and long noncoding RNA (lncRNA)-sequencing. Plasma samples were analyzed using LC-MS/MS for metabolite shifts using a semitargeted metabolomics panel.

Results

Eleven patients with NIUA and 10 healthy controls were recruited. The mRNA gene profiles of predesensitization versus postdesensitization and healthy control versus postdesensitization did not differ significantly. However, we identified 739 mRNAs and 888 lncRNAs as differentially expressed from preaspirin desensitization patients and controls. A 12-mRNA gene signature was trained using a machine learning algorithm to distinguish between controls, postdose, and predose samples. Ingenuity Pathway Analysis identified 5 canonical pathways that were significantly enriched in preaspirin desensitization samples. IL-22 was the most upregulated pathway. To investigate the potential regulatory roles of the differentially expressed lncRNA on the mRNAs, 9 lncRNAs and 12 mRNAs showed significantly correlated expression patterns in the IL-22 pathway. To validate the transcriptomics data, IL-22 was measured in the plasma samples of the subjects using ELISA. IL-22 was significantly higher in preaspirin desensitization patients compared with controls. In parallel, metabolomic analysis revealed stark differences in plasma profiles of preaspirin desensitization patients and healthy controls. In particular, 2-hydroxybenzoic acid (salicylic acid) was significantly lower in preaspirin desensitization patients compared with healthy controls.

Conclusions

This is the first study to combine both transcriptomic and metabolomic approaches in patients with NIUA, which contributes to a deeper understanding about the pathogenesis of NIUA and may potentially pave the way toward a molecular diagnosis of NSAID hypersensitivity.

中文翻译：

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不同的转录组学和代谢组学特征表征了接受阿司匹林脱敏治疗的非甾体抗炎药诱发的荨麻疹/血管性水肿患者

背景

非甾体类抗炎药 (NSAID) 诱发的荨麻疹/血管性水肿 (NIUA) 患者阿司匹林脱敏机制的数据有限。

目标

我们试图描述接受阿司匹林脱敏治疗的 NIUA 患者的转录组学和代谢组学特征。

方法

PBMC 和血浆是从接受阿司匹林脱敏治疗冠状动脉疾病的 NIUA 患者和 NSAID 耐受对照的血液中分离出来的。从 PBMC 中分离出 RNA，并对其进行信使 RNA (mRNA) 和长链非编码 RNA (lncRNA) 测序。使用 LC-MS/MS 使用半靶向代谢组学面板分析血浆样品的代谢物变化。

结果

招募了 11 名 NIUA 患者和 10 名健康对照者。脱敏前与脱敏后以及健康对照与脱敏后的 mRNA 基因谱没有显着差异。然而，我们鉴定了 739 种 mRNA 和 888 种 lncRNA，它们在前阿司匹林脱敏患者和对照组中有差异表达。使用机器学习算法训练 12-mRNA 基因特征，以区分对照、给药后和给药前样本。Ingenuity Pathway Analysis 确定了 5 条典型途径，这些途径在前阿司匹林脱敏样品中显着丰富。IL-22 是最上调的途径。为了研究差异表达的 lncRNA 对 mRNA 的潜在调控作用，9 个 lncRNA 和 12 个 mRNA 在 IL-22 通路中表现出显着相关的表达模式。为了验证转录组学数据，使用 ELISA 测量了受试者血浆样本中的 IL-22。与对照组相比，前阿司匹林脱敏患者的 IL-22 显着更高。同时，代谢组学分析揭示了前阿司匹林脱敏患者和健康对照者血浆特征的明显差异。特别是，与健康对照组相比，前阿司匹林脱敏患者的 2-羟基苯甲酸（水杨酸）含量显着降低。

结论

这是第一项在 NIUA 患者中结合转录组学和代谢组学方法的研究，这有助于更深入地了解 NIUA 的发病机制，并可能为 NSAID 超敏反应的分子诊断铺平道路。