Genetic Causal Inference Between Inflammatory Proteins and Osteoporosis and the Mediating Effects of Immune Cell Phenotypes:A Mendelian Randomization Study

doi:10.3870/j.issn.1672-0741.25.08.010

Abstract

Abstract: Objective To investigate the causal relationships between inflammatory proteins,immune cell-mediated pathways,and osteoporosis using a two-step two-sample Mendelian randomization(MR)approach. Methods This MR study leveraged large-scale genome-wide association studies(GWAS)to analyze 91 inflammatory proteins as exposures,731 immune cell phenotypes as potential mediators,and osteoporosis as the outcome.Inverse variance weighted(IVW)regression served as the primary statistical method,complemented by multilayered sensitivity analyses to enhance robustness. Results The inverse variance weighted method showed that four inflammatory proteins were significantly associated with osteoporosis,all exhibiting positive correlations with disease risk.Among 48 immune cell phenotypes significantly linked to osteoporosis,29 showed positive associations,and 19 showed negative associations with disease risk.Reverse Mendelian randomization analysis revealed no significant correlations,and sensitivity analyses identified no evidence of substantial heterogeneity or horizontal pleiotropy.Furthermore,mediation analysis demonstrated that BAFF-R on IgD^-CD38br partially mediated the causal effect between ARTN(β=0.051,OR=1.053,P=0.002)and osteoporosis.The mediation effect was 0.002,the mediating proportion was 3.9%,and the direct effect was 0.049. Conclusion Mendelian randomization analysis provided supporting evidence for bidirectional causal relationships between inflammatory proteins and osteoporosis,identifying that ARTN may drive osteoporosis development via increasing BAFF-R on IgD^-CD38br.

Key words: osteoporosis, inflammatory protein, immune cell, Mendelian randomization, mediation analysis

CLC Number:

R681.4

Rao Hao, Wu Gang, Zhang Xuxing et al. Genetic Causal Inference Between Inflammatory Proteins and Osteoporosis and the Mediating Effects of Immune Cell Phenotypes:A Mendelian Randomization Study[J]. Acta Medicinae Universitatis Scientiae et Technologiae Huazhong, 2026, 55(2): 204-213.

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