Causal relationship between Interleukin-27 expression levels and osteoporosis: a bidirectional mendelian...

Area of Science:

• Genetics and Molecular Biology
• Immunology
• Bone Biology

Background:

• Osteoporosis is a significant public health concern characterized by reduced bone density and increased fracture risk.
• The role of specific cytokines, such as Interleukin-27 (IL-27), in the pathogenesis of osteoporosis remains incompletely understood.

Purpose of the Study:

• To investigate the potential causal relationship between Interleukin-27 (IL-27) levels and osteoporosis.
• To explore the directionality of this relationship using a bidirectional Mendelian randomization (MR) approach.

Main Methods:

• Utilized genome-wide association study (GWAS) summary data for osteoporosis and IL-27 levels from the IEU OpenGWAS database.
• Performed bidirectional MR analysis employing MR-Egger, Weighted Median, Simple Mode, Weighted Mode, and Inverse Variance Weighted (IVW) methods.
• Conducted sensitivity analyses including heterogeneity, horizontal pleiotropy tests, and Leave-One-Out analysis to ensure result robustness.
• Performed gene enrichment analysis for SNPs associated with IL-27 levels to identify biological pathways involved.

Main Results:

• Bidirectional MR analysis indicated that higher IL-27 levels are a significant causal risk factor for osteoporosis (P=0.004, OR=1.123).
• No significant causal relationship was found between osteoporosis and IL-27 levels in the reverse direction (P>0.05).
• Sensitivity analyses confirmed the reliability of the forward MR results, showing no significant heterogeneity or horizontal pleiotropy.
• Enrichment analysis identified 74 genes linked to IL-27 levels, primarily involved in immune and inflammatory pathways.

Conclusions:

• IL-27 is causally associated with an increased risk of osteoporosis.
• IL-27 may contribute to osteoporosis development and progression via immune and inflammatory mechanisms.
• These findings provide a basis for further research into IL-27's role in osteoporosis pathogenesis.