血浆miRNA与过敏性鼻炎之间的因果关联：一项双样本孟德尔随机化与功能富集研究。

文献信息

中文摘要

目的： 过敏性鼻炎是一种由复杂免疫失调驱动的常见炎症性疾病。尽管已知循环miRNA是基因表达的调节因子，但其在过敏性鼻炎发病机制中的具体因果作用在很大程度上仍未明确。
方法： 我们进行了一项全面的双样本孟德尔随机化分析，以研究血浆miRNA对过敏性鼻炎的因果效应。遗传工具来自大规模miRNA eQTL数据集。因果估计主要使用GWAS目录数据集中的过敏性鼻炎汇总统计量进行评估，并在独立的FinnGen队列（15,569例病例和474,650例对照）中进行了稳健验证。进行了敏感性分析，包括贝叶斯共定位和反向孟德尔随机化，以确保有效性。通过预测靶标的富集分析探索了下游机制。
结果： 我们确定了多个miRNA的显著因果关联。值得注意的是，miR-130a-3p在多个队列中被一致验证为过敏性鼻炎的风险因素，而miR-1908-5p、miR-146a-3p和miR-6891-3p则表现出保护作用。共定位分析为miR-148a-3p和miR-181家族共享遗传变异提供了提示性证据，且未发现反向因果关系的证据。功能富集分析显示，这些miRNA的靶基因显著参与Wnt信号通路、MAPK信号通路、黏着斑和神经发生，提示它们参与上皮屏障调节和神经源性炎症。
结论： 本研究为循环miRNA与过敏性鼻炎风险之间潜在的因果关联提供了遗传学支持，并优先将miR-130a-3p和miR-1908-5p作为值得进一步功能验证的候选调节因子。
证据等级： 5级。就证据等级而言，孟德尔随机化（MR）研究仅次于随机对照试验。

英文摘要

OBJECTIVE: Allergic rhinitis is a prevalent inflammatory disorder driven by complex immune dysregulation. While circulating miRNAs are known regulators of gene expression, their specific causal roles in the pathogenesis of allergic rhinitis remain largely undefined.
METHODS: We performed a comprehensive two-sample Mendelian randomization analysis to investigate the causal effect of plasma miRNAs on allergic rhinitis. Genetic instruments were obtained from large-scale miRNA eQTL datasets. Causal estimates were primarily evaluated using allergic rhinitis summary statistics from the GWAS catalog dataset and robustly validated in the independent FinnGen cohort (15,569 cases and 474,650 controls). Sensitivity analyses, including Bayesian colocalization and reverse Mendelian randomization, were conducted to ensure validity. Downstream mechanisms were explored via enrichment analyses of predicted targets.
RESULTS: We identified significant causal associations for multiple miRNAs. Notably, miR-130a-3p was consistently validated as a risk factor for allergic rhinitis across cohorts, whereas miR-1908-5p, miR-146a-3p, and miR-6891-3p exhibited protective effects. Colocalization analysis offered suggestive evidence of shared genetic variants for miR-148a-3p and the miR-181 family, with no evidence of reverse causality. Functional enrichment analysis revealed that target genes of these miRNAs are significantly involved in Wnt signaling, MAPK signaling, focal adhesion, and neurogenesis, implicating them in epithelial barrier regulation and neurogenic inflammation.
CONCLUSIONS: This study provides genetic support for potential causal associations between circulating miRNAs and allergic rhinitis risk, prioritizing miR-130a-3p and miR-1908-5p as candidate regulators that warrant further functional validation.
LEVEL OF EVIDENCE: Level 5. Mendelian Randomized (MR) studies are second only to randomized controlled trials in terms of the level of evidence.