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. 2025 Jun 6:18:3219-3232.
doi: 10.2147/JMDH.S524949. eCollection 2025.

Causal Effects of Immune Cells on Reproductive Ill-Health, Including Abnormal Spermatozoa, Polycystic Ovary Syndrome and Spontaneous Abortion: Mendelian Randomization Analyses

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 Guo  1
Affiliations

Causal Effects of Immune Cells on Reproductive Ill-Health, Including Abnormal Spermatozoa, Polycystic Ovary Syndrome and Spontaneous Abortion: Mendelian Randomization Analyses

Shuang Chen et al. J Multidiscip Healthc. .

Abstract

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; abnormal spermatozoa; causal inference; immunity; polycystic ovary syndrome; spontaneous abortion.

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Conflict of interest statement

The authors declare that they have no competing interests in this work.

Figures

Figure 1
Figure 1
Overview of the study design. (A) Schematic representation of the three core assumptions underlying MR analysis: Assumption 1: The correlation hypothesis: genetic variation is directly related to exposure; Assumption 2: The Independence hypothesis: there is no connection between the genetic variant and the possible confounders between exposure and outcome; Assumption 3: The exclusion hypothesis: the genetic variation will not affect the outcome by means other than exposure. (B) Flowchart outlining the overall study design.
Figure 2
Figure 2
Causal associations between immune traits and AS: Results of MR analyses using the IVW method.
Figure 3
Figure 3
Causal associations between immune traits and PCOS: Results of MR analyses using the IVW method.
Figure 4
Figure 4
Causal associations between immune traits and SA: Results of MR analyses using the IVW method.
See this image and copyright information in PMC

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