Asthma increased the risk of atrial fibrillation: insights from clinical association to genetic and molecular evidence

BACKGROUND: Despite the high global incidence of asthma and atrial fibrillation (AF), the causal relationship between the two conditions remains unclear. Emerging observational evidence suggests a potential association; however, conflicting results and limited mechanistic insights necessitate a comprehensive evaluation. This study aims to determine the causal relationship between asthma and the risk of AF and to explore the underlying molecular mechanisms. METHODS: We performed a meta-analysis of observational studies to assess the association between asthma and AF risk, followed by a two-sample Mendelian randomization (MR) analysis to infer causality. Bioinformatics analyses using data from the Gene Expression Omnibus (GEO) were conducted to identify differentially expressed genes (DEGs) and enriched pathways. Potential therapeutic targets were validated through drug-gene interaction screening. RESULTS: The meta-analysis of eight observational studies involving 1,067,774 participants demonstrated that asthma was associated with a 21% increased risk of AF (odds ratio (OR) = 1.21, 95% confidence interval (CI): 1.07-1.36, p = 0.003). Two-sample MR analyses of European populations revealed that genetically predicted asthma was causally associated with increased AF risk (inverse-variance weighted (IVW) OR = 1.001, 95% CI: 1.000-1.002, p = 0.019), whereas no significant association was observed in East Asian cohorts. Transcriptomic analyses identified carboxypeptidase A3 (CPA3) as a shared upregulated gene in both asthma and AF, potentially involved in renin-angiotensin system dysregulation. Drug-gene interaction screening suggested osilodrostat and metyrapone as potential therapeutic candidates targeting CPA3. CONCLUSIONS: Our study provides evidence that genetic predisposition to asthma is significantly associated with an increased risk of AF in the European population. Transcriptomic data analyses suggest that CPA3 and its interactions with therapeutic drugs could serve as potential biomarkers, offering new opportunities to improve prognosis in patients with coexisting asthma and AF.