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

Abstract

BackgroundThe impact of inflammatory factors on the development of Ankylosing Spondylitis (AS) is widely recognized, but the exact causal relationship remains unclear.MethodsThe 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.ResultsThe results suggest a genetically predicted potential association between beta-nerve growth factor (βNGF), Interleukin-1-beta (IL-1β), 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, Interleukin-12p70 (IL-12p70), Interleukin-17 (IL-17), Interleukin-6 (IL-6), Interleukin-4 (IL-4), Stromal-cell-derived factor 1 alpha (SDF−1α), Macrophage inflammatory protein 1β (MIP1β), 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 -γ) 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.ConclusionThese findings suggest that βNGF, IL-1β, 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−1α, MIP1β, MCP-3, PDGFbb,GCSF, bFGF,TRAIL,and IFN-γ. Further investigations are warranted to determine whether these biomarkers can be utilized for the prevention or treatment of AS.

Exploring causal correlations between inflammatory cytokines and knee osteoarthritis: a two-sample Mendelian randomization

“…First, we set P <5×10 -8 as the genome-wide significance threshold to select SNPs that were strongly associated with KOA and inflammatory cytokines. Because very few SNPs were identified for some of the cytokines upon exposure, a higher cutoff value ( P <5×10 -6 ) to ensure that there were enough SNPs for further MR analysis ( 40 , 41 ). Secondly, to avoid linkage disequilibrium, instrumental variables were removed to ensure mutual independence of these instrumental variables (r2 = 0.001, kb=10,000).…”

Exploring causal correlations of inflammatory biomarkers in idiopathic normal-pressure hydrocephalus: insights from bidirectional Mendelian randomization analysis

“…GWAS data for these 41 inflammatory cytokines can be found in the IEU Open GWAS project 1 with corresponding GWAS IDs. Another 91 inflammatory cytokine GWAS were derived from a genome-wide protein quantitative trait locus study of circulating inflammatory proteins in 14,824 individuals of European ancestry (Zhao et al, 2023), including 11 study cohorts such as The INTERVAL study (median age 61 years). GWAS data for these 91 inflammatory factors are available through the GWAS Catalog project 2 with corresponding GWAS IDs.…”

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“…GWAS data for these 41 inflammatory cytokines can be found in the IEU Open GWAS project 1 with corresponding GWAS IDs. Another 91 inflammatory cytokine GWAS were derived from a genome-wide protein quantitative trait locus study of circulating inflammatory proteins in 14,824 individuals of European ancestry (Zhao et al, 2023), including 11 study cohorts such as The INTERVAL study (median age 61 years). GWAS data for these 91 inflammatory factors are available through the GWAS Catalog project 2 with corresponding GWAS IDs.…”