Circulating inflammatory proteins as causal drivers and therapeutic targets in asthma: insights from genetic and pathway-based analyses

To identify circulating inflammatory proteins with potential causal roles in asthma development through integrated genetic and pathway-based analyses, and to evaluate their potential as therapeutic targets. We used genetically anchored instrumental variables from 180 protein quantitative trait loci (pQTLs) to assess the causal effects of 91 circulating inflammatory proteins on asthma risk, using large-scale GWAS datasets. Analytical robustness was evaluated through pleiotropy and heterogeneity testing. Functional enrichment and literature-based pathway analyses were performed to support biological plausibility and validate findings. Four proteins showed significant causal effects on asthma: CCL19 and LIFR were protective (OR = 0.89 and 0.91, <i>p</i> ≤ 6.8E-03), while ARTN and IL6 were associated with increased risk (OR = 1.15 and 1.18, <i>p</i> ≤ 1.1E-04). We also identified reverse causal effects of asthma on 11 cytokines, including MMP10, TGFB1, IL33, and IL18R1. Most of these proteins were enriched in pathways related to cytokine signaling and immune response (<i>p</i> &lt; 0.001). All identified proteins had prior literature support linking them to asthma or airway inflammation. Our findings highlight a subset of circulating inflammatory proteins that are likely causal in asthma pathogenesis and may serve as promising targets for therapeutic intervention. These results offer novel insights into the immunological mechanisms underlying asthma and support the utility of genetic causal inference in target prioritization.

本研究旨在通过整合遗传学与基于通路的分析方法，识别在哮喘发生发展中具有潜在因果作用的循环炎症蛋白，并评估其作为治疗靶点的潜力。我们依托来自180个蛋白数量性状位点（protein quantitative trait loci, pQTLs）的遗传锚定工具变量，结合大规模全基因组关联研究（Genome-Wide Association Study, GWAS）数据集，对91种循环炎症蛋白的哮喘风险因果效应进行评估。通过多效性与异质性检验分析了研究结果的稳健性。同时开展功能富集分析与基于文献的通路分析，以验证研究发现的生物学合理性。研究结果显示，4种蛋白对哮喘具有显著因果效应：CCL19与LIFR为保护性因素（比值比[Odds Ratio, OR]分别为0.89与0.91，p ≤ 6.8×10⁻³），而ARTN与IL6则与哮喘风险升高相关（OR分别为1.15与1.18，p ≤ 1.1×10⁻⁴）。此外，本研究还识别到哮喘可对11种细胞因子产生反向因果效应，包括MMP10、TGFB1、IL33与IL18R1。上述多数蛋白富集于细胞因子信号通路与免疫应答相关通路（p < 0.001）。所有已识别的蛋白均有既往文献支持其与哮喘或气道炎症存在关联。本研究结果提示，部分循环炎症蛋白在哮喘发病机制中具有潜在因果作用，有望成为极具前景的治疗干预靶点。上述发现为哮喘的免疫发病机制提供了全新见解，并证实了遗传因果推断在治疗靶点优先筛选中的应用价值。