Genetically Predicted Gut Microbial Taxa and Inflammatory Proteins Associated With Atrial Fibrillation: A Bidirectional Mendelian Randomization and Colocalization Study.

BACKGROUND: Observational studies have linked the gut microbiota and inflammatory proteins to atrial fibrillation (AF), but confounding, reverse causation, and instrument validity remain concerns. METHODS: We evaluated 473 microbial traits and 91 inflammatory proteins in relation to AF using two GWAS datasets. Sensitivity analyses included instruments selected at p < 5 × 10-8, MR-RAPS, cis/trans-stratified protein MR, reverse MR, and FGF-5 colocalization. Participants were predominantly of European ancestry. RESULTS: Under conventional IVW analysis, six associations were FDR-significant in the discovery analysis and remained FDR-significant when selectively evaluated in the second AF GWAS, with FDR correction applied across the six prioritized tests: Leptospirae (OR 0.605, 95% CI 0.457-0.800), Leptospirales (0.499, 0.371-0.673), leukemia inhibitory factor receptor (LIF-R; 0.905, 0.869-0.943), TWEAK (0.891, 0.856-0.927), FGF-5 (1.077, 1.051-1.103), and interleukin-6 (0.886, 0.834-0.942). At p < 5 × 10-8, neither microbial trait had a harmonized instrument, whereas the protein estimates retained their directions. MR-RAPS supported LIF-R in both datasets, but support for the other signals varied. The prioritized proteins also differed in cis/trans genetic architecture. The FGF-5 cis-only estimates were based on two harmonized instruments and were therefore preliminary, while cis-region colocalization provided little evidence of a shared variant (PP.H4 = 0.0045). CONCLUSIONS: The conventional IVW associations varied in robustness across alternative analyses. These findings prioritize hypotheses, not established causal pathways or clinical targets. Generalizability beyond predominantly European populations remains uncertain.