Dong Kai-Xuan, Mo Jia-Hang, Yan Jing, Cheng Yi, Chen Hui-Xi, Xu Nai-Xin, Dou Zhi-Yuan, Zhu Hong, Zhu Lan, Huang He-Feng
Departments of Obstetrics and Gynecology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
Research Units of Embryo Original Diseases, Chinese Academy of Medical Sciences (No. 2019RU056), Shanghai, China.
BMC Pregnancy Childbirth. 2025 Feb 22;25(1):195. doi: 10.1186/s12884-025-07318-4.
Previous studies suggested that immune factors may play critical roles in female infertility, but their causal links remain unclear. To address this gap, this study employs the Mendelian randomization (MR) to delineate the causal association between circulating immune factors and female infertility.
This study employed summary-level data from three genome-wide association studies (GWAS) encompassing 731 peripheral immune cell signatures, 41 circulating cytokines, and five female infertility phenotypes to reveal the causal relationship between immune factors and female infertility. Causalities of exposure-outcome pairs were explored mainly using two-sample MR, and comprehensive sensitivity analyses were deployed to validate the reliability of the results. Multi-variable Mendelian randomization (MVMR) was further employed to examine the potential mediating effects between significant exposures.
Following false discovery rate (FDR) correction and sensitivity analyses, univariable Mendelian randomization identified distinct causal immune signatures across infertility subtypes. Peripheral levels of Naive CD8br %CD8br, MIP1B and IL17 were causally associated with general female infertility, and higher circulating MIP1B level decreased the risk of ovarian infertility. Furthermore, peripheral levels of CD80 on monocyte and MIP1B were causally associated with a higher risk of tubal infertility, three peripheral immune cell features (CD86 + myeloid DC AC, HLA DR + NK %NK, CD16 on CD14- CD16 + monocyte) were causal for uterine factor infertility, and three cytokines (MIP1B, IL18, IL17) were genetic causes of cervical infertility, vaginal infertility, other or unspecified origin infertility (FIOTHNAS). MVMR further revealed that MIP1B's effects on general female infertility and FIOTHNAS were substantially attenuated upon adjusting for circulating levels of IL17 and IL18.
Our results highlight that immune response contributes to female infertility risk through subtype-specific mechanisms, providing clues for following clinical research and treatment.
以往研究表明免疫因素可能在女性不孕症中起关键作用，但其因果关系仍不明确。为填补这一空白，本研究采用孟德尔随机化（MR）方法来阐明循环免疫因素与女性不孕症之间的因果关联。
本研究利用来自三项全基因组关联研究（GWAS）的汇总水平数据，这些数据涵盖731种外周免疫细胞特征、41种循环细胞因子和五种女性不孕症表型，以揭示免疫因素与女性不孕症之间的因果关系。暴露-结局对的因果关系主要采用两样本MR进行探索，并进行全面的敏感性分析以验证结果的可靠性。进一步采用多变量孟德尔随机化（MVMR）来检验显著暴露之间的潜在中介作用。
经过错误发现率（FDR）校正和敏感性分析后，单变量孟德尔随机化在不同不孕症亚型中确定了不同的因果免疫特征。幼稚CD8br%CD8br、MIP1B和IL17的外周水平与女性总体不孕症存在因果关联，循环中较高的MIP1B水平降低了卵巢性不孕症的风险。此外，单核细胞上CD80的外周水平和MIP1B与输卵管性不孕症的较高风险存在因果关联，三种外周免疫细胞特征（CD86+髓样DC AC、HLA DR+NK%NK、CD14-CD16+单核细胞上的CD16）是子宫因素不孕症的病因，三种细胞因子（MIP1B、IL18、IL17）是宫颈性不孕症、阴道性不孕症、其他或未明确起源不孕症（FIOTHNAS）的遗传病因。MVMR进一步显示，在调整IL17和IL18的循环水平后，MIP1B对女性总体不孕症和FIOTHNAS的影响显著减弱。
我们的结果突出表明免疫反应通过亚型特异性机制导致女性不孕症风险，为后续的临床研究和治疗提供了线索。
