{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,29]],"date-time":"2026-10-29T03:46:31Z","timestamp":1793245591851,"version":"4.5.0"},"reference-count":30,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,12,17]],"date-time":"2025-12-17T00:00:00Z","timestamp":1765929600000},"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>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>\n                      To investigate the dynamic genetic regulatory mechanisms of CD4\n                      <jats:sup>+<\/jats:sup>\n                      T cells in the pathogenesis of obstructive sleep apnea (OSA), particularly in the immune and inflammatory response induced by intermittent hypoxia (IH).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      This study integrated context-specific expression quantitative trait locus analysis, Mendelian randomization, colocalization analysis, single-cell RNA sequencing, and qPCR experimental validation. A systematic investigation was conducted on gene expression and genetic variation in CD4\n                      <jats:sup>+<\/jats:sup>\n                      T cells obtained from 119 donors of European descent across multiple activation time points including zero hours, sixteen hours, forty hours, and five days. Functional validation was performed using an IH mouse model.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      The study identified multiple genes demonstrating a causal relationship with OSA risk, such as\n                      <jats:italic>MAST3<\/jats:italic>\n                      ,\n                      <jats:italic>FNBP4<\/jats:italic>\n                      ,\n                      <jats:italic>SPNS1<\/jats:italic>\n                      , and\n                      <jats:italic>AKIRIN1<\/jats:italic>\n                      . Thirteen expression quantitative trait loci showed significant colocalization with OSA genome-wide association study signals, with a posterior probability of shared causal variants exceeding zero point eight five. Experimental validation in the IH mouse model demonstrated significantly upregulated mRNA expression levels of\n                      <jats:italic>Fnbp4<\/jats:italic>\n                      and\n                      <jats:italic>Mast3<\/jats:italic>\n                      , alongside downregulated expression of\n                      <jats:italic>Sgf29<\/jats:italic>\n                      ,\n                      <jats:italic>Sh3yl1<\/jats:italic>\n                      , and\n                      <jats:italic>Tufm<\/jats:italic>\n                      within CD4\n                      <jats:sup>+<\/jats:sup>\n                      T cells.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      The immune regulation mediated by CD4\n                      <jats:sup>+<\/jats:sup>\n                      T cells demonstrates significant temporal dynamics and cell type specificity in OSA pathogenesis. Key genes including\n                      <jats:italic>TUFM<\/jats:italic>\n                      ,\n                      <jats:italic>MAST3<\/jats:italic>\n                      ,\n                      <jats:italic>FNBP4<\/jats:italic>\n                      ,\n                      <jats:italic>SGF29<\/jats:italic>\n                      , and\n                      <jats:italic>SH3YL1<\/jats:italic>\n                      participate in the pathological process by regulating mitochondrial function, cell migration, transcriptional regulation, and inflammatory responses. These findings provide a novel theoretical foundation and reveal potential targets for personalized therapeutic strategies and biomarker development in OSA.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2025.1691347","type":"journal-article","created":{"date-parts":[[2025,12,17]],"date-time":"2025-12-17T06:36:13Z","timestamp":1765953373000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":4,"title":["Dynamic genetic regulation of CD4+ T cells in obstructive sleep apnea: integrating context-specific eQTL, Mendelian randomization, single-cell sequencing, and experimental validation"],"prefix":"10.3389","volume":"16","author":[{"given":"Xinyue","family":"Zhang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lingfei","family":"Ren","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,12,17]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1016\/S2213-2600(19)30198-5","article-title":"Estimation of the global prevalence and burden of obstructive sleep apnoea: a literature-based analysis","volume":"7","author":"Benjafield","year":"2019","journal-title":"Lancet Respir Med"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2016.11.069","article-title":"Sleep apnea: types, mechanisms, and clinical cardiovascular consequences","volume":"69","author":"Javaheri","year":"2017","journal-title":"J Am Coll Cardiol"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2022.812974","article-title":"Prevalence and characteristics of erectile dysfunction in obstructive sleep apnea patients","volume":"13","author":"Feng","year":"2022","journal-title":"Front Endocrinol (Lausanne)"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2025.06.023","article-title":"S aureus upregulation of MUC13 modulates mucosal remodeling in chronic rhinosinusitis via MEK1\/2 and WNT2B","volume":"156","author":"Feng","year":"2025","journal-title":"J Allergy Clin Immunol"},{"key":"B5","doi-asserted-by":"publisher","first-page":"104536","DOI":"10.1016\/j.ebiom.2023.104536","article-title":"Genome-wide association study of obstructive sleep apnoea in the Million Veteran Program uncovers genetic heterogeneity by sex","volume":"90","author":"Sofer","year":"2023","journal-title":"EBioMedicine"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1016\/j.jgg.2025.02.003","article-title":"Expression quantitative trait loci (eQTL): from population genetics to precision medicine","volume":"52","author":"Wong","year":"2025","journal-title":"J Genet Genomics"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-022-04713-1","article-title":"Single-cell eQTL models reveal dynamic T cell state dependence of disease loci","volume":"606","author":"Nathan","year":"2022","journal-title":"Nature"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2017.17219","article-title":"Mendelian randomization","volume":"318","author":"Emdin","year":"2017","journal-title":"JAMA"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1126\/science.abf3041","article-title":"Single-cell eQTL mapping identifies cell type-specific genetic control of autoimmune disease","volume":"376","author":"Yazar","year":"2022","journal-title":"Science"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-022-01066-3","article-title":"Immune disease risk variants regulate gene expression dynamics during CD4+ T cell activation","volume":"54","author":"Soskic","year":"2022","journal-title":"Nat Genet"},{"key":"B11","doi-asserted-by":"publisher","first-page":"38","DOI":"10.1038\/nbt.4314","article-title":"Dimensionality reduction for visualizing single-cell data using UMAP","volume":"37","author":"Becht","year":"2019","journal-title":"Nat Biotechnol"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.5664\/jcsm.3070","article-title":"Serum inflammatory markers in obstructive sleep apnea: a meta-analysis","volume":"9","author":"Nadeem","year":"2013","journal-title":"J Clin Sleep Med"},{"key":"B13","doi-asserted-by":"publisher","first-page":"95","DOI":"10.1016\/j.sleep.2007.11.013","article-title":"Exhaled breath condensate cytokine level as a diagnostic tool for obstructive sleep apnea syndrome","volume":"10","author":"Li","year":"2009","journal-title":"Sleep Med"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.962175","article-title":"Modeling the effect of environmental cytokines, nutrient conditions and hypoxia on CD4(+) T cell differentiation","volume":"13","author":"Martinez-Mendez","year":"2022","journal-title":"Front Immunol"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.3389\/fphys.2023.1108966","article-title":"A novel OSA-related model of intermittent hypoxia in endothelial cells under flow reveals pronounced inflammatory pathway activation","volume":"14","author":"Muller","year":"2023","journal-title":"Front Physiol"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1038\/s41418-021-00868-y","article-title":"Autophagy-competent mitochondrial translation elongation factor TUFM inhibits caspase-8-mediated apoptosis","volume":"29","author":"Choi","year":"2022","journal-title":"Cell Death Differ"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1016\/j.yexcr.2017.03.034","article-title":"Mitochondria control acute and chronic responses to hypoxia","volume":"356","author":"McElroy","year":"2017","journal-title":"Exp Cell Res"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2022.848214","article-title":"Mitochondrial dynamics, mitophagy, and mitochondria-endoplasmic reticulum contact sites crosstalk under hypoxia","volume":"10","author":"Wang","year":"2022","journal-title":"Front Cell Dev Biol"},{"key":"B19","doi-asserted-by":"publisher","first-page":"11913","DOI":"10.3390\/ijms241511913","article-title":"Microtubule-associated serine\/threonine (MAST) kinases in development and disease","volume":"24","author":"Rumpf","year":"2023","journal-title":"Int J Mol Sci"},{"key":"B20","doi-asserted-by":"publisher","first-page":"a002261","DOI":"10.1101\/cshperspect-a002261","article-title":"The coordination of T-cell function by serine\/threonine kinases","volume":"3","author":"Finlay","year":"2011","journal-title":"Cold Spring Harb Perspect Biol"},{"key":"B21","doi-asserted-by":"publisher","first-page":"108550","DOI":"10.1016\/j.jbc.2025.108550","article-title":"Nuclear protein FNBP4: A novel inhibitor of non-diaphanous formin FMN1-mediated actin cytoskeleton dynamics","volume":"301","author":"Das","year":"2025","journal-title":"J Biol Chem"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2018.00389","article-title":"The Formin mDia1 Regulates Acute Lymphoblastic Leukemia Engraftment, Migration, and Progression in vivo","volume":"8","author":"Thompson","year":"2018","journal-title":"Front Oncol"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.3892\/etm.2017.4971","article-title":"Intermittent hypoxia simulating obstructive sleep apnea causes pulmonary inflammation and activates the Nrf2\/HO-1 pathway","volume":"14","author":"Wang","year":"2017","journal-title":"Exp Ther Med"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1016\/j.surg.2011.06.035","article-title":"Alveolar macrophage activation in obese patients with obstructive sleep apnea","volume":"151","author":"Sharma","year":"2012","journal-title":"Surgery"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1038\/emboj.2011.193","article-title":"Sgf29 binds histone H3K4me2\/3 and is required for SAGA complex recruitment and histone H3 acetylation","volume":"30","author":"Bian","year":"2011","journal-title":"EMBO J"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1016\/j.freeradbiomed.2024.12.021","article-title":"NADPH oxidase 4-SH3 domain-containing YSC84-like 1 complex participates liver inflammation and fibrosis","volume":"227","author":"Hur","year":"2025","journal-title":"Free Radic Biol Med"},{"key":"B27","doi-asserted-by":"publisher","first-page":"108245","DOI":"10.1016\/j.celrep.2020.108245","article-title":"LPS-induced acute kidney injury is mediated by nox4-SH3YL1","volume":"33","author":"Yoo","year":"2020","journal-title":"Cell Rep"},{"key":"B28","doi-asserted-by":"publisher","first-page":"88","DOI":"10.1378\/chest.13-2288","article-title":"Antiinflammatory therapy outcomes for mild OSA in children","volume":"146","author":"Kheirandish-Gozal","year":"2014","journal-title":"Chest"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1378\/chest.14-1988","article-title":"Repeated polysomnograms after antiinflammatory therapy of mild pediatric OSA","volume":"146","author":"Traeger","year":"2014","journal-title":"Chest"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1111\/resp.13564","article-title":"Advanced polysomnographic analysis for OSA: A pathway to personalized management","volume":"25","author":"de Chazal","year":"2020","journal-title":"Respirology"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2025.1691347\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,17]],"date-time":"2025-12-17T06:36:17Z","timestamp":1765953377000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2025.1691347\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,12,17]]},"references-count":30,"alternative-id":["10.3389\/fimmu.2025.1691347"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2025.1691347","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,12,17]]},"article-number":"1691347"}}