Causal relationship between circulating inflammatory factors and osteoporosis: a bidirectional Mendelian...

Area of Science:

• Genetics and Molecular Biology
• Immunology
• Bone Metabolism

Background:

• Osteoporosis (OP) is a metabolic bone disorder with an unclear etiology, often associated with inflammation.
• Investigating the causal relationship between inflammation and OP is crucial for understanding disease pathogenesis.

Purpose of the Study:

• To employ bidirectional Mendelian randomization (MR) to explore the causal interplay between circulating inflammatory modulators and osteoporosis.
• To identify specific inflammatory factors that influence the risk of developing osteoporosis.

Main Methods:

• Conducted two-way pooled-level MR analyses using genetic variation data from genome-wide association studies (GWASs) of 41 human cytokines.
• Utilized bone mineral density (BMD) as a phenotype for OP, with data from the GEFOS consortium and UK Biobank across various skeletal sites and age groups.
• Employed inverse variance weighting (IVW) for primary analysis and MR-Egger, weighted median, simple, and weighted models for sensitivity analyses, alongside heterogeneity and pleiotropy assessments.

Main Results:

• Elevated levels of interleukin-8 (IL-8), macrophage inflammatory protein-1b (MIP-1β), and cutaneous T-cell attracting chemokine (CTACK) were associated with a decreased risk of OP.
• Reduced levels of hepatocyte growth factor (HGF), IL-1ra, IL-10, macrophage colony-stimulating factor (MCSF), and MIP-1α were linked to a lower risk of OP.
• A significant causal correlation was observed between femoral neck BMD and MCP-3, with OP occurrence potentially increasing MCP3 levels.

Conclusions:

• Bidirectional MR analysis confirmed the pathogenic role of specific circulating inflammatory modulators in osteoporosis.
• Findings deepen the understanding of OP pathogenesis and suggest novel therapeutic intervention strategies targeting inflammatory pathways.