{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,16]],"date-time":"2026-01-16T10:43:23Z","timestamp":1768560203281,"version":"3.49.0"},"reference-count":74,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,10,13]],"date-time":"2023-10-13T00:00:00Z","timestamp":1697155200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>Antiphospholipid syndrome (APS) is a group of clinical syndromes of thrombosis or adverse pregnancy outcomes caused by antiphospholipid antibodies, which increase the incidence of <jats:italic>in vitro<\/jats:italic> fertilization failure in patients with infertility. However, the common mechanism of repeated implantation failure (RIF) with APS is unclear. This study aimed to search for potential diagnostic genes and potential therapeutic targets for RIF with APS.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>To obtain differentially expressed genes (DEGs), we downloaded the APS and RIF datasets separately from the public Gene Expression Omnibus database and performed differential expression analysis. We then identified the common DEGs of APS and RIF. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses were performed, and we then generated protein-protein interaction. Furthermore, immune infiltration was investigated by using the CIBERSORT algorithm on the APS and RIF datasets. LASSO regression analysis was used to screen for candidate diagnostic genes. To evaluate the diagnostic value, we developed a nomogram and validated it with receiver operating characteristic curves, then analyzed these genes in the Comparative Toxicogenomics Database. Finally, the Drug Gene Interaction Database was searched for potential therapeutic drugs, and the interactions between drugs, genes, and immune cells were depicted with a Sankey diagram.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>There were 11 common DEGs identified: four downregulated and seven upregulated. The common DEG analysis suggested that an imbalance of immune system-related cells and molecules may be a common feature in the pathophysiology of APS and RIF. Following validation, MARK2, CCDC71, GATA2, and KLRC3 were identified as candidate diagnostic genes. Finally, Acetaminophen and Fasudil were predicted as two candidate drugs.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Four immune-associated candidate diagnostic genes (MARK2, CCDC71, GATA2, and KLRC3) were identified, and a nomogram for RIF with APS diagnosis was developed. Our findings may aid in the investigation of potential biological mechanisms linking APS and RIF, as well as potential targets for diagnosis and treatment.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2023.1126103","type":"journal-article","created":{"date-parts":[[2023,10,13]],"date-time":"2023-10-13T05:06:41Z","timestamp":1697173601000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":10,"title":["Identification of MARK2, CCDC71, GATA2, and KLRC3 as candidate diagnostic genes and potential therapeutic targets for repeated implantation failure with antiphospholipid syndrome by integrated bioinformatics analysis and machine learning"],"prefix":"10.3389","volume":"14","author":[{"given":"Manli","family":"Zhang","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ting","family":"Ge","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yunian","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaolin","family":"La","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2023,10,13]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"28","DOI":"10.1016\/j.rbmo.2017.04.004","article-title":"The effect of endometrial scratch on natural-cycle cryopreserved embryo transfer outcomes: a randomized controlled study","volume":"35","author":"Mak","year":"2017","journal-title":"Reprod BioMed Online"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1093\/humrep\/deac105.056","article-title":"Assisted reproductive technology (ART) in Europe 2019 and development of a strategy of vigilance Preliminary results generated from European registers by the ESHRE EIM consortium","volume":"37","author":"Wyns","year":"2022","journal-title":"Hum Reprod"},{"key":"B3","doi-asserted-by":"publisher","first-page":"14","DOI":"10.1016\/j.rbmo.2013.08.011","article-title":"Recurrent implantation failure: definition and management","volume":"28","author":"Coughlan","year":"2014","journal-title":"Reprod BioMed Online"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2021.613277","article-title":"Approaches to improve endometrial receptivity in case of repeated implantation failures","volume":"9","author":"Makrigiannakis","year":"2021","journal-title":"Front Cell Dev Biol"},{"key":"B5","doi-asserted-by":"publisher","first-page":"103080","DOI":"10.1016\/j.jri.2020.103080","article-title":"The uterine immunological changes may be responsible for repeated implantation failure","volume":"138","author":"Amjadi","year":"2020","journal-title":"J Reprod Immunol"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1016\/j.medcli.2020.12.023","article-title":"Does incomplete obstetric antiphospholipid syndrome really exist","volume":"156","author":"Alijotas-Reig","year":"2021","journal-title":"Med Clinica"},{"key":"B7","doi-asserted-by":"publisher","first-page":"54","DOI":"10.1007\/s12016-016-8569-0","article-title":"Pregnancy outcome in women with obstetric and thrombotic antiphospholipid syndrome-A retrospective analysis and a review of additional treatment in pregnancy","volume":"53","author":"Mayer-Pickel","year":"2017","journal-title":"Clin Rev Allergy Immunol"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1080\/14767058.2018.1535586","article-title":"In vitro fertilization outcomes in women with antiphospholipid antibodies circulation","volume":"33","author":"Khizroeva","year":"2020","journal-title":"J Maternal-Fetal Neonatal Med"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-0897.2006.00437.x","article-title":"Influence of antiphospholipid antibodies on pregnancy outcome in women undergoing in vitro fertilization and embryo transfer","volume":"57","author":"Lee","year":"2007","journal-title":"Am J Reprod Immunol"},{"key":"B10","doi-asserted-by":"crossref","DOI":"10.1196\/annals.1422.048","article-title":"Antigenic profile, prevalence, and clinical significance of antiphospholipid antibodies in women referred for in vitro fertilization","volume-title":"Ann NY Acad Sci","author":"Sanmarco","year":"2007"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1600305","article-title":"beta 2 glycoprotein I recognition drives th1 inflammation in atherosclerotic plaques of patients with primary antiphospholipid syndrome","volume":"198","author":"Benagiano","year":"2017","journal-title":"J Immunol"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1097\/GCO.0b013e3283294879","article-title":"Is there a role of autoimmunity in implantation failure after","volume":"21","author":"Cline","year":"2009","journal-title":"in-vitro fertilization? 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