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Genetic influences of the effect of circulating inflammatory cytokines on osteoarthritis in humans

  • Author Footnotes
    b These authors contributed equally to this work.
    G. Huang
    Footnotes
    b These authors contributed equally to this work.
    Affiliations
    Department of Joint Surgery, The First Affiliated Hospital of Sun Yat-sen University, Sun Yat-sen University, Guangzhou, China

    Guangdong Provincial Key Laboratory of Orthopedics and Tramatology, The First Affiliated Hospital of Sun Yat-sen University, Sun Yat-sen University, Guangzhou, China
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  • Author Footnotes
    a Co-first author.
    ,
    Author Footnotes
    b These authors contributed equally to this work.
    W. Li
    Footnotes
    a Co-first author.
    b These authors contributed equally to this work.
    Affiliations
    Department of Joint Surgery, The First Affiliated Hospital of Sun Yat-sen University, Sun Yat-sen University, Guangzhou, China

    Guangdong Provincial Key Laboratory of Orthopedics and Tramatology, The First Affiliated Hospital of Sun Yat-sen University, Sun Yat-sen University, Guangzhou, China
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  • H. Kan
    Affiliations
    Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
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  • X. Lu
    Affiliations
    Department of Joint Surgery, The First Affiliated Hospital of Sun Yat-sen University, Sun Yat-sen University, Guangzhou, China

    Guangdong Provincial Key Laboratory of Orthopedics and Tramatology, The First Affiliated Hospital of Sun Yat-sen University, Sun Yat-sen University, Guangzhou, China
    Search for articles by this author
  • W. Liao
    Affiliations
    Department of Joint Surgery, The First Affiliated Hospital of Sun Yat-sen University, Sun Yat-sen University, Guangzhou, China

    Guangdong Provincial Key Laboratory of Orthopedics and Tramatology, The First Affiliated Hospital of Sun Yat-sen University, Sun Yat-sen University, Guangzhou, China
    Search for articles by this author
  • X. Zhao
    Correspondence
    Address correspondence and reprint requests to: X. Zhao, Department of Joint Surgery, Guangdong Provincial Key Laboratory of Orthopedics and Tramatology, The First Affiliated Hospital of Sun Yat-sen University, Sun Yat-sen University, Guangzhou, China.
    Affiliations
    Department of Joint Surgery, The First Affiliated Hospital of Sun Yat-sen University, Sun Yat-sen University, Guangzhou, China

    Guangdong Provincial Key Laboratory of Orthopedics and Tramatology, The First Affiliated Hospital of Sun Yat-sen University, Sun Yat-sen University, Guangzhou, China
    Search for articles by this author
  • Author Footnotes
    a Co-first author.
    b These authors contributed equally to this work.
Published:December 16, 2022DOI:https://doi.org/10.1016/j.joca.2022.12.007

      Summary

      Objective

      The causal relationship between inflammatory cytokines and Osteoarthritis (OA) has not been well investigated. This study investigated the causal role of inflammatory cytokines in the risk of OA and total joint arthroplasty using the Mendelian randomization (MR) method.

      Method

      Single nucleotide polymorphisms (SNPs) robustly associated with inflammatory cytokines were used as instrumental variables. The inverse-variance weighted (IVW) method with false discovery rate (FDR) adjusted P-value (q-value) for multiple comparisons were used as the main MR method to estimate causal effects based on the summary-level data for OA (knee and hip OA, respectively) and total joint arthroplasty (TJA). Sensitivity analyses validated the robustness of the results and ensured the absence of heterogeneity and horizontal pleiotropy.

      Results

      After FDR adjustment, macrophage colony-stimulating factor (MCSF) and vascular endothelial growth factor (VEGF) were identified as causally associated with knee OA (MCSF, odds ratio [OR]: 1.16, 95% confidence interval [CI]: 1.09–1.23, q = 5.05 × 10−5; VEGF, OR: 1.09, 95% CI: 1.04–1.15, q = 0.011). We also observed that genetically predicted MCSF and VEGF were positively associated with the risk of TJA, and MCP3 was negatively associated with for the risk of TJA, although the effects seem fairly modest. Sensitivity analysis further excluded the influence of heterogeneity and horizontal pleiotropy.

      Conclusions

      Inflammatory cytokines, namely MCSF and VEGF, were causally associated with knee OA, which could enhance our understanding of inflammation in OA pathology.

      Keywords

      Abbreviations:

      MR (Mendelian randomization), GWAS (Genome-wide association studies), IVW (Inverse-variance weighted), MR-PRESSO (MR pleiotropy residual sum and outlier), SNP (Nucleotide polymorphism), OA (Osteoarthritis), TJA (Total joint arthroplasty), TKA (Total knee arthroplasty), THA (Total hip arthroplasty), MMP3 (Monocyte chemotactic protein-3), MCSF (Macrophage colony-stimulating factor), VEGF (Vascular endothelial growth factor), activePAI (Active plasminogen activator inhibitor), CTACK (Cutaneous T-cell attracting chemokine), GROa (Growth-regulated oncogene-alpha), HGF (Hepatocyte growth factor), MIG (Monokine induced by interferon-gamma), MIP (Macrophage inflammatory protein), PDGFbb (Platelet-derived growth factor BB), RANTES (Regulated upon activation, normal T cell expressed and secreted), SCF (Stem cell factor), SCGFb (Stem cell growth factor beta), SeSelectin (Soluble E-selectin), sICAM (Soluble intercellular adhesion molecule), TRAIL (TNF-related apoptosis inducing ligand)
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