Genetically predicted circulating immune cells and cytokines reveal the causal role of immune factors on female infertility: a two-sample mendelian randomization study.

Publisher: BioMed Central Country of Publication: England NLM ID: 100967799 Publication Model: Electronic Cited Medium: Internet ISSN: 1471-2393 (Electronic) Linking ISSN: 14712393 NLM ISO Abbreviation: BMC Pregnancy Childbirth Subsets: MEDLINE

Original Publication: London : BioMed Central, [2001-

Mendelian Randomization Analysis* ; Genome-Wide Association Study* ; Infertility, Female*/genetics ; Infertility, Female*/immunology ; Infertility, Female*/blood ; Cytokines*/blood ; Cytokines*/genetics; Humans ; Female ; Polymorphism, Single Nucleotide

Objectives: 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.
Methods: 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.
Results: 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.
Conclusion: Our results highlight that immune response contributes to female infertility risk through subtype-specific mechanisms, providing clues for following clinical research and treatment.
Competing Interests: Declarations. Ethics approval and consent to participate: Data used in this study was provided by the Finngen R9 release and published GWAS study, thus the ethical approval and informed consent have been approved by the corresponding ethical review board. Additionally, no individual-level data was used in this study. Thus, no ethical approval was required. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests.
(© 2025. The Author(s).)

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82088102 the National Natural Science Foundation of China; 82088102 the National Natural Science Foundation of China; 2021YFC2700603 National Key R&D Program of China; 2021YFC2700603 National Key R&D Program of China; 2021YFC2700603 National Key R&D Program of China; 2019-I2M-5-064 CAMS Innovation Fund for Medical Sciences; 2019-I2M-5-064 CAMS Innovation Fund for Medical Sciences; 2019-I2M-5-064 CAMS Innovation Fund for Medical Sciences; 2020CXJQ01 Collaborative Innovation Program of Shanghai Municipal Health Commission; GWVI-11.1-35 Key Discipline Construction Project (2023-2025) of Three-Year Initiative Plan for Strengthening Public Health System Construction in Shanghai; 22MC1940200 Clinical Research Plan of SHDC (SHDC2020CR1008A), Shanghai Clinical Research Center for Gynecological Diseases; 2022ZZ01012 Shanghai Urogenital System Diseases Research Center

Keywords: Causal inference; Cytokines; Female infertility; Immunity; Mendelian randomization

0 (Cytokines)

Date Created: 20250222 Date Completed: 20250223 Latest Revision: 20250225

20250225

PMC11847394

10.1186/s12884-025-07318-4

39987435