Unraveling the genetic basis of the causal association between inflammatory cytokines and osteonecrosis

Abstract

Background: Previous studies have reported that the occurrence and development of osteonecrosis is closely associated with immune-inflammatory responses. Mendelian randomization was performed to further assess the causal correlation between 41 inflammatory cytokines and osteonecrosis.

Methods: Two-sample Mendelian randomization utilized genetic variants for osteonecrosis from a large genome-wide association study (GWAS) with 606 cases and 209,575 controls of European ancestry. Another analysis included drug-induced osteonecrosis with 101 cases and 218,691 controls of European ancestry. Inflammatory cytokines were sourced from a GWAS abstract involving 8,293 healthy participants. The causal relationship between exposure and outcome was primarily explored using an inverse variance weighting approach. Multiple sensitivity analyses, including MR-Egger, weighted median, simple model, weighted model, and MR-PRESSO, were concurrently applied to bolster the final results.

Results: The results showed that bFGF, IL-2 and IL2-RA were clinically causally associated with the risk of osteonecrosis (OR=1.942, 95% CI=1.13-3.35, p=0.017; OR=0.688, 95% CI=0.50-0.94, p=0.021; OR=1.386, 95% CI=1.04-1.85, p = 0.026). there was a causal relationship between SCF and drug-related osteonecrosis (OR=3.356, 95% CI=1.09-10.30, p=0.034).

Conclusion: This pioneering Mendelian randomization study is the first to explore the causal link between osteonecrosis and 41 inflammatory cytokines. It conclusively establishes a causal association between osteonecrosis and bFGF, IL-2, and IL-2RA. These findings offer valuable insights into osteonecrosis pathogenesis, paving the way for effective clinical management. The study suggests bFGF, IL-2, and IL-2RA as potential therapeutic targets for osteonecrosis treatment.

Keywords: GWAS; bone; immune; inflammation; mendelian randomization; necrosis.

Figure 1

Schematic diagram of the study design in this Mendelian randomization (MR) analysis. Forty-one important instrumental variables for inflammatory cytokines and osteonecrosis were selected and then explored for bidirectional causality. The three basic assumptions of MR analysis, namely correlation, independence, and exclusionary restrictions, are illustrated in this causally directed acyclic graph.

Figure 2

Causal correlations of 41 inflammatory cytokines on osteonecrosis. The change in the odds ratio (OR) of osteonecrosis per one-SD rise in the cytokine level is shown by OR and 95% confidence interval. P-value 0.05/41 = 0.0012 was found significant after multiple-comparison correction. The results from the inverse variance weighted method were shown for all cytokines. bNGF, beta nerve growth factor; CTACK, cutaneous T cell-attracting chemokine; FGFBasic, basic fibroblast growth factor; GCSF, granulocyte colony-stimulating factor; GROa, growth-regulated oncogene-a; HGF, hepatocyte growth factor; IFNg, interferon gamma; IL, interleukin; IP, interferon gamma-induced protein 10; MCP1, monocyte chemotactic protein 1; MCP3, monocyte-specific chemokine 3; MCSF, macrophage colony-stimulating factor; MIF, macrophage migration inhibitory factor; MIG, monokine induced by interferon gamma; MIP1a, macrophage inflammatory protein-1a; MIP1b, macrophage inflammatory protein-1b; PDGFbb, platelet-derived growth factor BB; RANTES, regulated upon activation normal T cell expressed and secreted factor; SCF, stem cell factor; SCGFb, stem cell growth factor beta; SDF1a, stromal cell-derived factor-1 alpha; SNPs, single-nucleotide polymorphisms; TNFa, tumor necrosis factor alpha; TNFb, tumor necrosis factor beta; TRAIL, TNF-related apoptosis-inducing ligand; VEGF, vascular endothelial growth factor.

Figure 3

Causal correlations of 41 inflammatory cytokines on drug-induced osteonecrosis. The change in the odds ratio (OR) of drug-induced osteonecrosis per one-SD rise in the cytokine level is shown by OR and 95% confidence interval. P-value 0.05/41 = 0.0012 was found significant after multiple-comparison correction. The results from the inverse variance weighted method were shown for all cytokines.

Figure 4

Causal estimation of bFGF, IL-2, IL-2RA and SCF on osteonecrosis and its drug-induced subtype. Forest plots depict the causal estimates of bFGF, IL-2, IL-2RA and SCF on osteonecrosis and its drug-induced subtypes. The dominance ratio (OR) was estimated using the fixed-effects IVW method. Horizontal bars indicate 95% confidence intervals (CI).

Figure 5

The immune inflammatory response plays a critical role in the development and progression of osteonecrosis. Various adverse factors trigger a chronic immune inflammatory response, resulting in sustained production of pro-inflammatory cytokines, progressive tissue damage, and abnormal tissue remodeling. In necrotic bone tissue, inflammatory cytokines and chemokines attract innate immune cells and adaptive immune cells, which release additional inflammatory cytokines in a positive feedback loop to amplify the overall inflammatory response. Furthermore, chronic inflammation excessively activates bone resorption, inhibits bone formation, and drives osteonecrosis.