Genetically Predicted Circulating Inflammatory Proteins and Risk of Atrial Fibrillation: A Two-Sample Mendelian Randomization Study

Heer Rashmikant Donda

doi:10.36948/ijfmr.2026.v08i04.85401

Genetically Predicted Circulating Inflammatory Proteins and Risk of Atrial Fibrillation: A Two-Sample Mendelian Randomization Study

Author(s)	Ms. Heer Rashmikant Donda
Country	Hong Kong
Abstract	Background Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia, and systemic inflammation has been repeatedly linked to its incidence in observational studies. However, distinguishing causal biological pathways from downstream inflammatory responses remains incompletely defined. Observational studies have identified numerous inflammatory biomarkers associated with AF, but these associations are susceptible to confounding and reverse causation. Mendelian randomization (MR) uses inherited genetic variants as instrumental variables to estimate the causal effects of genetically proxied differences in circulating protein concentrations. Methods A two-sample Mendelian randomization (MR) study of circulating inflammatory proteins and AF risk was performed. Protein instruments were derived from Sun et al. (2018) plasma proteome genome-wide association study (GWAS; European ancestry, n=3,301). From 284 pre-specified inflammatory protein exposures, 177 yielded complete instrument sets and were taken forward for analysis. Summary statistics for AF were drawn from Nielsen et al. (2018) AF GWAS (OpenGWAS ID: ebi-a-GCST006414; 60,620 cases, 970,216 controls; n=1,030,836). Primary causal estimates were obtained using the inverse-variance weighted (IVW) method for proteins instrumented by two or more single nucleotide polymorphisms (SNPs) and the Wald ratio for single-SNP instruments. Sensitivity analyses included MR-Egger regression, weighted median, weighted mode, simple mode, Cochran’s Q heterogeneity testing, Steiger directionality testing, leave-one-out analyses and single-SNP influence analyses where applicable; MR-PRESSO was only applicable to exposures with sufficient instrument numbers. F-statistics were used to evaluate instrument strengths. Bonferroni correction was applied across the 177 analysed proteins (threshold p < 0.05/177 ≈ 2.82 × 10⁻⁴), alongside false discovery rate (FDR) correction. Results Among the 284 inflammatory proteins examined, five associations remained significant after Bonferroni correction and two additional proteins met an FDR-robust threshold. Genetically predicted higher circulating levels of interleukin-6 receptors, captured independently by three overlapping instruments (prot-b-23, prot-a-1540, prot-a-1541), were inversely associated with AF risk (odds ratio [OR] range 0.951-0.966). Tumor necrosis factor ligand superfamily member 12 (TNFSF12) was inversely associated with AF (OR 0.895, 95% CI 0.861-0.929), while platelet-derived growth factor subunit B (PDGFB) was positively associated (OR 1.198, 95% CI 1.088-1.319). At the FDR-robust tier, insulin-like growth factor I (IGF-I) was associated with reduced AF risk (OR 0.923, 95% CI 0.878–0.970). Platelet-derived growth factor subunit A (PDGFA) was positively associated (OR 1.126, 95% CI 1.051-1.206). All seven associations were supported by F-statistics above the conventional weak-instrument threshold and passed Steiger directionality filtering, while only the multi-SNP exposures permitted fuller heterogeneity and pleiotropy assessment. An additional 20 proteins showed nominal, uncorrected associations and are reported only in the supplement. Conclusions This large-scale proteome-wide Mendelian randomization analysis identified genetically predicted variation in multiple inflammatory proteins associated with AF susceptibility. These findings support a potential role for the IL-6 receptor signaling axis, platelet-derived growth factor pathways, TNFSF12, and IGF-I in AF pathogenesis. The IL-6 receptor signals were the most internally consistent, whereas other associations were based on sparse instrumentation and should be interpreted more cautiously. While these results strengthen the causal inference compared with conventional observational studies, the sparse instrumentation for several exposures and absence of colocalisation analysis make these findings hypothesis-generating and require independent replication prior to any therapeutic inference being drawn.
Keywords	Mendelian randomization, atrial fibrillation, inflammatory proteins, IL-6 receptor, platelet-derived growth factor, insulin-like growth factor I, cardiovascular genetics, proteomics
Field	Biology > Genetics / Molecular
Published In	Volume 8, Issue 4, July-August 2026
Published On	2026-08-08
DOI	https://doi.org/10.36948/ijfmr.2026.v08i04.85401

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Genetically Predicted Circulating Inflammatory Proteins and Risk of Atrial Fibrillation: A Two-Sample Mendelian Randomization Study

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