Abstract：
BACKGROUND: Gene expression can provide distinct information compared to clinical biomarkers in the context of longitudinal clinical outcomes in asthma patients.
OBJECTIVE: This study examined the association between the gene expression levels of upstream (IL-25, IL-33, and TSLP) and downstream cytokines (IL-5, IL-4, and IL-13) in the T2 inflammatory pathway with a 12-month follow-up of exacerbation, lung function, and steroid use.
METHODS: Transcriptomic sequencing analysis was performed on peripheral blood mononuclear cells from 279 adult asthmatics. Survival analysis and linear mixed-effect models were used to investigate potential differences between the high-level and low-level gene expression groups and the clinical outcomes. Analysis was performed separately for the upstream, downstream, and all 6 cytokines.
RESULTS: In general, T2 inflammatory cytokine gene expression showed a weak correlation with blood eosinophil counts (all r < 0.1) and clinical outcomes. Among moderate-to-severe eosinophilic asthma (MSEA) patients, individuals with elevated levels of downstream cytokines were at increased risk of time-to-first exacerbation (p = 0.044) and a greater increase of inhaled corticosteroid use over time (p = 0.002) compared to those with lower gene expression. There was no association between baseline T2 inflammatory cytokine gene expression and the longitudinal changes in lung function over time among MSEA patients.
CONCLUSIONS: These findings suggest that, among MSEA patients, the gene expression levels of downstream cytokines in the T2 inflammatory pathway may serve as indicators for endotyping asthma.
OBJECTIVE: This study examined the association between the gene expression levels of upstream (IL-25, IL-33, and TSLP) and downstream cytokines (IL-5, IL-4, and IL-13) in the T2 inflammatory pathway with a 12-month follow-up of exacerbation, lung function, and steroid use.
METHODS: Transcriptomic sequencing analysis was performed on peripheral blood mononuclear cells from 279 adult asthmatics. Survival analysis and linear mixed-effect models were used to investigate potential differences between the high-level and low-level gene expression groups and the clinical outcomes. Analysis was performed separately for the upstream, downstream, and all 6 cytokines.
RESULTS: In general, T2 inflammatory cytokine gene expression showed a weak correlation with blood eosinophil counts (all r < 0.1) and clinical outcomes. Among moderate-to-severe eosinophilic asthma (MSEA) patients, individuals with elevated levels of downstream cytokines were at increased risk of time-to-first exacerbation (p = 0.044) and a greater increase of inhaled corticosteroid use over time (p = 0.002) compared to those with lower gene expression. There was no association between baseline T2 inflammatory cytokine gene expression and the longitudinal changes in lung function over time among MSEA patients.
CONCLUSIONS: These findings suggest that, among MSEA patients, the gene expression levels of downstream cytokines in the T2 inflammatory pathway may serve as indicators for endotyping asthma.
摘要：
背景：在哮喘患者的纵向临床结果的背景下，与临床生物标志物相比，基因表达可以提供不同的信息。
目的：本研究通过对急性加重12个月的随访，研究了T2炎症通路中上游细胞因子（IL-25、IL-33和TSLP）和下游细胞因子（IL-5、IL-4和IL-13）的基因表达水平之间的关联，肺功能,和类固醇的使用。
方法：对来自279名成人哮喘患者的外周血单核细胞进行转录组测序分析。使用生存分析和线性混合效应模型来研究高水平和低水平基因表达组和临床结果之间的潜在差异。分别对上游进行分析，下游,和所有6种细胞因子。
结果：一般来说，T2炎性细胞因子基因表达与血嗜酸性粒细胞计数(均r<0.1)和临床结局呈弱相关性。在中度至重度嗜酸性粒细胞哮喘（MSEA）患者中，与基因表达较低的患者相比,下游细胞因子水平升高的患者出现首次加重时间的风险增加(p=0.044),并且随着时间的推移,吸入性皮质类固醇使用量增加更多(p=0.002).在MSEA患者中，基线T2炎性细胞因子基因表达与肺功能随时间的纵向变化之间没有关联。
结论：这些发现表明，在MSEA患者中，T2炎症通路下游细胞因子的基因表达水平可作为哮喘分型的指标.
目的：本研究通过对急性加重12个月的随访，研究了T2炎症通路中上游细胞因子（IL-25、IL-33和TSLP）和下游细胞因子（IL-5、IL-4和IL-13）的基因表达水平之间的关联，肺功能,和类固醇的使用。
方法：对来自279名成人哮喘患者的外周血单核细胞进行转录组测序分析。使用生存分析和线性混合效应模型来研究高水平和低水平基因表达组和临床结果之间的潜在差异。分别对上游进行分析，下游,和所有6种细胞因子。
结果：一般来说，T2炎性细胞因子基因表达与血嗜酸性粒细胞计数(均r<0.1)和临床结局呈弱相关性。在中度至重度嗜酸性粒细胞哮喘（MSEA）患者中，与基因表达较低的患者相比,下游细胞因子水平升高的患者出现首次加重时间的风险增加(p=0.044),并且随着时间的推移,吸入性皮质类固醇使用量增加更多(p=0.002).在MSEA患者中，基线T2炎性细胞因子基因表达与肺功能随时间的纵向变化之间没有关联。
结论：这些发现表明，在MSEA患者中，T2炎症通路下游细胞因子的基因表达水平可作为哮喘分型的指标.
