Qunhui Yin,* Kai Li,* Rong Chen,* Xin Li, Wai Leung Ambrose Lo, Qiuhua Yu, Minghui Ding, Siyun Zhang, Chuhuai Wang

Department of Rehabilitation Medicine, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 510080, People’s Republic of China

*These authors contributed equally to this work

Correspondence: Siyun Zhang; Chuhuai Wang, Email zhangsy63@mail.sysu.edu.cn; wangchuh@mail.sysu.edu.cn

Purpose: Osteoporosis is closely related to specific immune cell, yet the causal mechanism has not been clarified. Previous studies mostly adopted traditional unidirectional Mendelian randomization (MR) for analysis, failing to fully clarify their relationship. This study is the first to analyze the bidirectional causal relationship between the characteristics of peripheral immune cells and the risk of osteoporosis.
Methods: A bilateral two-sample MR was performed, with immune cells serving as instrumental variables and the incidence of osteoporosis as the outcome. We used five algorithms to evaluate the causal relationship between immune cells and the incidence of osteoporosis (inverse-variance weighted [IVW], MR-Egger, simple mode, weight median, and weight mode). The Cochran Q and leave-one-out tests were used to evaluate heterogeneity and stability, and the MR-Egger intercept test was used to evaluate horizontal pleiotropy.
Results: The eosinophil percentage of granulocytes (odds ratio [OR] = 1.25, 95% confidence interval [CI] = 1.08– 1.44, P = 0.002), eosinophil percentage of white cells (OR = 1.17, 95% CI = 1.02– 1.35, P = 0.027), and sum eosinophil basophil counts (OR = 1.16, 95% CI = 1.02– 1.32, P = 0.027) had positive causal associations with the incidence of osteoporosis. The lymphocyte counts (OR = 0.83, 95% CI = 0.71– 0.97, P = 0.016), neutrophil percentage of granulocytes (OR = 0.78, 95% CI = 0.67– 0.90, P < 0.001) played negative effect on osteoporosis. The reverse direction showed that osteoporosis had no causal effect on the characteristics of the immune cells. Non-significant heterogeneity and horizontal pleiotropy indicated the results were robust.
Conclusion: This study identified a unidirectional causal link between five immune cell traits and osteoporosis, providing new insights into osteoporosis pathogenesis and potential targeted immunotherapy.

Keywords: immune cells, osteoporosis, Mendelian randomization, genome-wide association study