Causal associations between plasma miRNAS and allergic rhinitis: A two-sample Mendelian randomization and functional enrichment study.

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.