Exploring causal correlations between inflammatory cytokines and ankylosing spondylitis: a bidirectional mendelian-randomization study

Background: The impact of inflammatory factors on the development of Ankylosing Spondylitis (AS) is widely recognized, but the exact causal relationship remains unclear.Methods: The bidirectional mendelian-randomization study utilized genetic data from a genome-wide association study (GWAS) of 186 AS cases and 456,162 controls of European ancestry. Inflammatory cytokines were obtained from a GWAS summary of 8,293 healthy participants. Causal associations were primarily investigated using the inverse variance-weighted method, supplemented by MR Egger, weighted median and weighted mode analyses. Heterogeneity in the results was assessed using the Cochrane Q test. Horizontal pleiotropy was evaluated through the MR-Egger intercept test and the MR pleiotropy residual sum and outliers (MR-PRESSO) test. Sensitivity analysis was conducted through leave-one-out analysis.Results: The results suggest a genetically predicted potential association between beta-nerve growth factor (bNGF), Interleukin-1-beta (IL-1b), and TNF-related apoptosis inducing ligand (TRAIL) with the risk of AS (OR: 2.17, 95% CI: 1.13-4.16; OR: 0.41, 95% CI: 0.18-0.95,; OR: 1.47, 95% CI: 1.02-2.13).Additionally, Interleukin12p70 (IL-12p70), Interleukin-17 (IL-17), Interleukin-6 (IL-6), Interleukin-4 (IL-4), Stromal-cell-derived factor 1 alpha (SDF-1a), Macrophage inflammatory protein 1b (MIP1b), Monocyte chemoattractant protein-3 (MCP-3), Platelet-derived growth factor bb (PDGFbb), Granulocyte-colony stimulating factor (GCSF), Fibroblast growth factor basic (bFGF), TNF-related apoptosis inducing ligand (TRAIL), and Interferon-gamma (IFN -gamma) are suggested as consequences of AS in genetically prediction. No evidence of horizontal pleiotropy or heterogeneity between the genetic variants was found (P>0.05), and a leave-one-out test confirmed the stability and robustness of this association. Conclusion: These findings suggest that bNGF, IL-1b, and TRAIL may play a crucial role in the pathogenesis of AS. Additionally, AS may impact the expression of cytokines such as IL-12p70, IL-17, IL-6, IL-4, SDF-1a, MIP1b, MCP-3, PDGFbb, GCSF, bFGF, TRAIL, and IFN-g. Further investigations are warranted to determine whether these biomarkers can be utilized for the prevention or treatment of AS.