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

Front Immunol. 2023 Nov 20:14:1285106. doi: 10.3389/fimmu.2023.1285106. eCollection 2023.

Abstract

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 (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.

Conclusion: These 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.

Keywords: GWAS; ankylosing spondylitis; inflammatory factors; mendelian randomization; single nucleotide polymorphisms.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Becaplermin
  • Chemokine CXCL12
  • Cytokines*
  • Genome-Wide Association Study
  • Granulocyte Colony-Stimulating Factor
  • Humans
  • Interferon-gamma
  • Interleukin-12
  • Interleukin-17
  • Interleukin-4
  • Interleukin-6
  • Ligands
  • Random Allocation
  • Spondylitis, Ankylosing* / genetics

Substances

  • Cytokines
  • Interleukin-17
  • Interleukin-4
  • Interleukin-6
  • Chemokine CXCL12
  • Ligands
  • Interleukin-12
  • Granulocyte Colony-Stimulating Factor
  • Interferon-gamma
  • Becaplermin

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This research received support from the Natural Science Foundation of Jiangsu Province (BK2022155) and the China Postdoctoral Science Foundation (No. 2021T140786). Additionally, funding was provided by the Medical Research Project of Jiangsu Provincial Health Care Commission (No. M2021051).