{"doi":"10.1111/aji.70061","title":"Causal Association Between Female Infertility and Circulating Immune Cells: A Bidirectional Mendelian Randomization Study","abstract":"<jats:title>ABSTRACT</jats:title><jats:sec><jats:title>Background</jats:title><jats:p>Female infertility (FI) is a global health issue. The etiology remains incompletely understood, but immunologic factors play important roles. This study aims to elucidate the causal association between FI and immune cells (ICs) via Mendelian randomization (MR) analysis.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>The MR analyses employ genetic variants as instrumental variables to evaluate exposure's causal impact on outcomes. In this study, the two‐sample MR method was performed to investigate the causal correlation of FI with 731 immunophenotypes of human peripheral blood lymphocytes. Complementary MR methods performed included the weighted median estimator (WME) and inverse variance weighted (IVW). In addition, sensitivity analyses were performed to assess and minimize heterogeneity and horizontal pleiotropy, and reverse MR analysis was used to assess reverse causality.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>The results revealed that four immune phenotypes were substantially linked with the risk of developing FI: CD33<jats:sup>dim</jats:sup> HLA DR+CD11b+%CD33<jats:sup>dim</jats:sup> HLA DR + (IVW: <jats:italic>p = 0.0396</jats:italic>, OR: 0.98 and WME: <jats:italic>p = 0.0208</jats:italic>, OR: 0.97), CD39+CD4+AC (IVW: <jats:italic>p = 0.0031</jats:italic>, OR: 1.03 and WME: <jats:italic>p = 0.0264</jats:italic>, OR: 1.03), CD27 on IgD‐CD38<jats:sup>bright</jats:sup> (IVW: <jats:italic>p = 0.0401</jats:italic>, OR: 0.93 and WME: <jats:italic>p = 0.0194</jats:italic>, OR: 0.90), CD28 on resting Treg (IVW: <jats:italic>p = 0.0019</jats:italic>, OR: 0.91 and WME: <jats:italic>p = 0.0128</jats:italic>, OR: 0.92). The main findings were validated by the sensitivity analyses, indicating data reliability.</jats:p></jats:sec><jats:sec><jats:title>Conclusions</jats:title><jats:p>In summary, this investigation carried out MR analysis to provide evidence suggesting a causal association between ICs and FI, thereby furnishing new literature on the disease as well as a basis for the establishment of immunomodulatory therapeutic avenues.</jats:p></jats:sec>","journal":"American Journal of Reproductive Immunology","year":2025,"id":625991,"datarank":0.10397207708399181,"base_score":0.6931471805599453,"endowment":0.6931471805599453,"self_citation_contribution":0.10397207708399181,"citation_network_contribution":0.0,"self_endowment_contribution":0.10397207708399181,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1619194,"name":"Yu‐Xuan Fang","orcid":null,"position":1,"is_corresponding":false},{"id":1619195,"name":"Li‐Ya Ma","orcid":null,"position":2,"is_corresponding":false},{"id":1619196,"name":"Da‐Wei Zhang","orcid":null,"position":3,"is_corresponding":false},{"id":1619197,"name":"Man‐Man Yao","orcid":null,"position":4,"is_corresponding":false},{"id":1288957,"name":"Xuan Zhou","orcid":"0000-0003-3429-6092","position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"Causal Association Between Female Infertility and Circulating Immune Cells: A Bidirectional Mendelian Randomization Study","abstract":"<jats:title>ABSTRACT</jats:title><jats:sec><jats:title>Background</jats:title><jats:p>Female infertility (FI) is a global health issue. The etiology remains incompletely understood, but immunologic factors play important roles. This study aims to elucidate the causal association between FI and immune cells (ICs) via Mendelian randomization (MR) analysis.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>The MR analyses employ genetic variants as instrumental variables to evaluate exposure's causal impact on outcomes. In this study, the two‐sample MR method was performed to investigate the causal correlation of FI with 731 immunophenotypes of human peripheral blood lymphocytes. Complementary MR methods performed included the weighted median estimator (WME) and inverse variance weighted (IVW). In addition, sensitivity analyses were performed to assess and minimize heterogeneity and horizontal pleiotropy, and reverse MR analysis was used to assess reverse causality.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>The results revealed that four immune phenotypes were substantially linked with the risk of developing FI: CD33<jats:sup>dim</jats:sup> HLA DR+CD11b+%CD33<jats:sup>dim</jats:sup> HLA DR + (IVW: <jats:italic>p = 0.0396</jats:italic>, OR: 0.98 and WME: <jats:italic>p = 0.0208</jats:italic>, OR: 0.97), CD39+CD4+AC (IVW: <jats:italic>p = 0.0031</jats:italic>, OR: 1.03 and WME: <jats:italic>p = 0.0264</jats:italic>, OR: 1.03), CD27 on IgD‐CD38<jats:sup>bright</jats:sup> (IVW: <jats:italic>p = 0.0401</jats:italic>, OR: 0.93 and WME: <jats:italic>p = 0.0194</jats:italic>, OR: 0.90), CD28 on resting Treg (IVW: <jats:italic>p = 0.0019</jats:italic>, OR: 0.91 and WME: <jats:italic>p = 0.0128</jats:italic>, OR: 0.92). The main findings were validated by the sensitivity analyses, indicating data reliability.</jats:p></jats:sec><jats:sec><jats:title>Conclusions</jats:title><jats:p>In summary, this investigation carried out MR analysis to provide evidence suggesting a causal association between ICs and FI, thereby furnishing new literature on the disease as well as a basis for the establishment of immunomodulatory therapeutic avenues.</jats:p></jats:sec>","is_dataset_classified":null,"base_score":0.6931471805599453,"endowment":0.6931471805599453,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"39998311","pmcid":null,"openalex_id":"https://openalex.org/W4407945179","authors":[],"funders":[{"funder_name":"Key Project of Traditional Chinese Medicine Scientific Research in Henan Province","grant_id":"2023ZYZD09","title":null},{"funder_name":"Henan Provincial Traditional Chinese Medicine Scientific Research Special Project","grant_id":"2024ZY2094","title":null},{"funder_name":"Henan Provincial Key Research and Development (Science and Technology Tackling) Project","grant_id":"222102310139","title":null}],"total_grants":3,"fwci":0.3867,"citation_percentile":0.5392178,"influential_citations":0,"citation_trend":[{"year":2025,"count":1}],"oa_status":"bronze","license":"http://onlinelibrary.wiley.com/termsAndConditions#vor","oa_locations":[{"url":"https://onlinelibrary.wiley.com/doi/pdfdirect/10.1111/aji.70061","host_type":"journal"},{"url":"https://onlinelibrary.wiley.com/doi/pdfdirect/10.1111/aji.70061","host_type":"publisher"},{"url":"https://onlinelibrary.wiley.com/doi/pdf/10.1111/aji.70061","host_type":"publisher"},{"url":"https://doi.org/10.1111/aji.70061","host_type":"journal"},{"url":"https://pubmed.ncbi.nlm.nih.gov/39998311","host_type":"repository"}],"fields_of_study":["Reproductive System and Pregnancy","Genetic Associations and Epidemiology","Sperm and Testicular Function"],"mesh_terms":["Female","Humans","Infertility, Female","Immunophenotyping","Genetic Predisposition to Disease","Polymorphism, Single Nucleotide","Mendelian Randomization Analysis"],"keywords":["Mendelian randomization","Pleiotropy","Immune system","Genome-wide association study","Genetic association","Biology","Immunology","Medicine","Genetics","Single-nucleotide polymorphism","Phenotype","Genetic variants","Genotype","Gene","Immune cells","Single Nucleotide Polymorphisms","Female Infertility","Mendelian Randomization Analysis","Sensitivity Analyses"],"sdg_mappings":[{"sdg_number":0,"sdg_label":"Good health and well-being"}],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[],"source":"live","citation_network_status":"fetched"},"created_at":"2026-08-04T11:52:04.537072Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}