Shuang Chen,1,* Shihao Sun,2,* Zihan Zhou,1,* Zhaokai Zhou,3 Ran Zhang,1 Wenyan Song,1 Hang Xin,1 Qingling Yang,1 Shanjun Dai,1 Kai Huang,1 Wenbin Niu,1 Hao Shi,1 Yihong Guo1 

1Center of Reproductive Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, People’s Republic of China; 2Department of Breast Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, People’s Republic of China; 3Department of Urology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, People’s Republic of China

*These authors contributed equally to this work

Correspondence: Yihong Guo, Center of Reproductive Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450052, People’s Republic of China, Email 13613863710@163.com

Background: Accumulative prior studies have demonstrated that immune inflammation profoundly influences reproductive disorders of mesodermal origin. However, little is known about the causal relationship between immune factors and diseases of the reproductive system.
Methods: Thorough two-sample Mendelian randomization (MR) analyses were conducted to determine the causal effects of 731 immune traits on reproductive ill-health, including abnormal spermatozoa (AS), polycystic ovary syndrome (PCOS), and spontaneous abortion (SA). Causal links were decrypted using genome-wide association study (GWAS) data. Sensitivity analyses were performed to assess the strength, heterogeneity, and horizontal pleiotropy of the results.
Results: For AS, 34 causal relationships were identified, with BAFF-R, CD20, and CD27 in the B-cell panel having protective effects against AS. A crucial causative connection between CD11c+ CD62L− monocyte%monocyte (cDC panel) and AS pathogenesis was also revealed. For PCOS, 40 causal effects were established, with CD20, CD24, and CD27 in the B-cell panel playing different roles in PCOS. CD4 on CM CD4+ (maturation stages of the T-cell panel) significantly increased the risk of PCOS. For SA, 33 causative associations were determined, and a protective effect of CCR2 (C-C chemokine receptor type 2) on CD14+ CD16+ monocytes (monocyte panel) in SA was particularly noted. The diverse functions of the CD28, CD39, and CD25 molecules in the Treg cell panel in SA were also observed.
Conclusion: This study comprehensively evaluated the causal impact of immune traits on reproductive illnesses, stressing the complex and important role of immunogenic factors in pathogenesis and highlighting a novel direction for clinical work.

Keywords: Mendelian randomization, immunity, causal inference, abnormal spermatozoa, polycystic ovary syndrome, spontaneous abortion