{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,14]],"date-time":"2026-05-14T06:42:08Z","timestamp":1778740928531,"version":"3.51.4"},"reference-count":64,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,8,29]],"date-time":"2025-08-29T00:00:00Z","timestamp":1756425600000},"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>Despite extensive genetic studies investigating primary biliary cholangitis (PBC), the mechanistic basis of risk-associated variants remains poorly understood. To address this gap, we performed a systematic evaluation of cumulative evidence linking genetic variants to PBC susceptibility.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>A comprehensive search was conducted to identify published studies on the association between genetic variants and PBC risk. Specifically, separate analyses were conducted for genome-wide association studies (GWASs) and candidate-gene association studies to address potential heterogeneity arising from differences in study design. Meta-analyses were performed to calculate pooled odds ratio (OR) and 95% confidence interval (CI) for the candidate-gene association studies. Significant associations were further graded using Venice criteria and false-positive report probability (FPRP) tests. Functional annotation, pathway enrichment, and phenome-wide analyses were performed to elucidate biological relevance.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Overall, we included 105 articles involving 71,031 cases and 140,499 controls. Meta-analyses were conducted for 70 variants across 33 genes. Among these, 44 variants were identified as significantly associated with PBC risk, comprising 30 HLA variants and 14 non-HLA variants. Separately, published GWAS have reported 115 significant variants. Nine variants (DQA1*0401, DQB1*0301, DQB1*0402, DQB1*0602, DRB1*08, DRB1*0803, DRB1*11, DRB1*1101, and rs7574865) were identified by both approaches. Additionally, meta-analyses of candidate-gene association studies provided strong evidence supporting the association of eight further variants (A*3303, B*4403, DPB1*0201, DQB1*0401, rs231725, rs231775, rs1544410, and rs9303277) with PBC at the genome-wide significance level (<jats:italic>P<\/jats:italic> &amp;lt; 5.0 \u00d7 10<jats:sup>-8<\/jats:sup>). Pathway analysis revealed significant enrichment of the mapped genes in immune cell regulation and immune response-regulating signaling pathways. Phenome-wide analyses further indicated that the missense variant rs231775 was significantly associated with thyroid problems and melanoma (<jats:italic>P<\/jats:italic>&amp;lt; 6.43\u00d710<jats:sup>-5<\/jats:sup>).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>This study provides the most comprehensive synopsis to date of PBC\u2019s genetic architecture, highlighting robust HLA and non-HLA risk loci.<\/jats:p><\/jats:sec><jats:sec><jats:title>Systematic review registration<\/jats:title><jats:p><jats:uri>https:\/\/\/www.crd.york.ac.uk\/PROSPERO\/view\/CRD42021282146<\/jats:uri>, identifier CRD42021282146.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2025.1600364","type":"journal-article","created":{"date-parts":[[2025,8,29]],"date-time":"2025-08-29T05:45:17Z","timestamp":1756446317000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":4,"title":["Genetic architecture of primary biliary cholangitis: strong evidence for HLA and non-HLA risk loci"],"prefix":"10.3389","volume":"16","author":[{"given":"Min","family":"Zhang","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Liang","family":"Lyu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Liang","family":"Ge","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yizhou","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dongqing","family":"Gu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2025,8,29]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaut.2018.10.015","article-title":"The immunobiology of female predominance in primary biliary cholangitis","volume":"95","author":"Gerussi","year":"2018","journal-title":"J Autoimmun"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cgh.2023.02.005","article-title":"New treatment paradigms in primary biliary cholangitis","volume":"21","author":"Levy","year":"2023","journal-title":"Clin Gastroenterol Hepatol"},{"key":"B3","doi-asserted-by":"publisher","first-page":"48","DOI":"10.1038\/s41395-018-0390-3","article-title":"Diagnosis and management of primary biliary cholangitis","volume":"114","author":"Younossi","year":"2019","journal-title":"Am J Gastroenterol"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa0810440","article-title":"Primary biliary cirrhosis associated with HLA, IL12A, and IL12RB2 variants","volume":"360","author":"Hirschfield","year":"2009","journal-title":"N Engl J Med"},{"key":"B5","doi-asserted-by":"publisher","first-page":"1732","DOI":"10.1038\/s41467-023-37213-5","article-title":"A regulatory variant at 19p13.3 is associated with primary biliary cholangitis risk and ARID3A expression","volume":"14","author":"Li","year":"2023","journal-title":"Nat Commun"},{"key":"B6","doi-asserted-by":"publisher","first-page":"8019","DOI":"10.1038\/ncomms9019","article-title":"International genome-wide meta-analysis identifies new primary biliary cirrhosis risk loci and targetab le pathogenic pathways","volume":"6","author":"Cordell","year":"2015","journal-title":"Nat Commun"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaut.2019.102372","article-title":"Fine mapping of the MHC region identifies major independent variants associated with Han Chinese primary biliary cholangitis","volume":"107","author":"Wang","year":"2020","journal-title":"J Autoimmun"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1038\/s41431-021-00854-5","article-title":"Regional heritability mapping identifies several novel loci (STAT4, ULK4, and KCNH5) for primary biliary cholangitis in the Japanese population","volume":"29","author":"Gervais","year":"2021","journal-title":"Eur J Hum Genet"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1038\/ng749","article-title":"Replication validity of genetic association studies","volume":"29","author":"Ioannidis","year":"2001","journal-title":"Nat Genet"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1093\/ije\/dym159","article-title":"Assessment of cumulative evidence on genetic associations: interim guidelines","volume":"37","author":"Ioannidis","year":"2008","journal-title":"Int J Epidemiol"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1093\/aje\/kwp119","article-title":"Genome-wide association studies, field synopses, and the development of the knowledge base on genetic variation and human diseases","volume":"170","author":"Khoury","year":"2009","journal-title":"Am J Epidemiol"},{"key":"B12","doi-asserted-by":"publisher","first-page":"17","DOI":"10.1038\/ng1934","article-title":"Systematic meta-analyses of Alzheimer disease genetic association studies: the AlzGene database","volume":"39","author":"Bertram","year":"2007","journal-title":"Nat Genet"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(11)70076-6","article-title":"Genetic variants associated with breast-cancer risk: comprehensive research synopsis, meta-analysis, and epidemiological evidence","volume":"12","author":"Zhang","year":"2011","journal-title":"Lancet Oncol"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1093\/jnci\/djr219","article-title":"Comprehensive field synopsis and systematic meta-analyses of genetic association studies in cutaneous melanoma","volume":"103","author":"Chatzinasiou","year":"2011","journal-title":"J Natl Cancer Inst"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1136\/gutjnl-2012-304121","article-title":"Genetic variants associated with colorectal cancer risk: comprehensive research synopsis, meta-analysis, and epidemiological evidence","volume":"63","author":"Ma","year":"2014","journal-title":"Gut"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1007\/s00251-020-01192-4","article-title":"Replication study and meta-analysis indicate a suggestive association of RUNX3 locus with primary biliary cholangitis","volume":"72","author":"Jawed","year":"2020","journal-title":"Immunogenetics"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1007\/s13258-018-0717-x","article-title":"Association between STAT4 polymorphisms and risk of primary biliary cholangitis: a meta-analysis","volume":"40","author":"Zhang","year":"2018","journal-title":"Genes Genomics"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1155\/2017\/5295164","article-title":"Genetic polymorphisms of cytotoxic T-lymphocyte antigen 4 in primary biliary cholangitis: A meta-analysis","volume":"2017","author":"Yang","year":"2017","journal-title":"J Immunol Res"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pmed.1000028","article-title":"Systematic reviews of genetic association studies","volume":"6","author":"Sagoo","year":"2009","journal-title":"Hum Genome Epidemiol Network. PloS Med"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.b2535","article-title":"Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement","volume":"339","author":"Moher","year":"2009","journal-title":"BMJ"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.7326\/0003-4819-127-9-199711010-00008","article-title":"Quantitative synthesis in systematic reviews","volume":"127","author":"Lau","year":"1997","journal-title":"Ann Intern Med"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.2307\/2533446","article-title":"Operating characteristics of a rank correlation test for publication bias","volume":"50","author":"Begg","year":"1994","journal-title":"Biometrics"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.315.7109.629","article-title":"Bias in meta-analysis detected by a simple, graphical test","volume":"315","author":"Egger","year":"1997","journal-title":"BMJ"},{"key":"B24","doi-asserted-by":"publisher","first-page":"498","DOI":"10.1002\/ijc.31074","article-title":"Cumulative evidence for relationships between multiple variants in the VTI1A and TCF7L2 genes and cancer incidence","volume":"142","author":"Zhang","year":"2018","journal-title":"Int J Cancer"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1093\/jnci\/djh075","article-title":"Assessing the probability that a positive report is false: an approach for molecular epidemiology studies","volume":"96","author":"Wacholder","year":"2004","journal-title":"J Natl Cancer Inst"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkr917","article-title":"HaploReg: a resource for exploring chromatin states, conservation, and regulatory motif alterations within sets of genetically linked variants","volume":"40","author":"Ward","year":"2012","journal-title":"Nucleic Acids Res"},{"key":"B27","doi-asserted-by":"publisher","first-page":"1826","DOI":"10.1038\/s41467-017-01261-5","article-title":"Functional mapping and annotation of genetic associations with FUMA","volume":"8","author":"Watanabe","year":"2017","journal-title":"Nat Commun"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gki475","article-title":"WebGestalt: an integrated system for exploring gene sets in various biological contexts","volume":"33","author":"Zhang","year":"2005","journal-title":"Nucleic Acids Res"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-018-0248-z","article-title":"An atlas of genetic associations in UK Biobank","volume":"50","author":"Canela-Xandri","year":"2018","journal-title":"Nat Genet"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms14828","article-title":"A genome-wide association study identifies six novel risk loci for primary biliary cholangitis","volume":"8","author":"Qiu","year":"2017","journal-title":"Nat Commun"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2021.04.055","article-title":"An international genome-wide meta-analysis of primary biliary cholangitis: Novel risk loci and candidate drugs","volume":"75","author":"Cordell","year":"2021","journal-title":"J Hepatol"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1038\/ng.2395","article-title":"Dense fine-mapping study identifies new susceptibility loci for primary biliary cirrhosis","volume":"44","author":"Liu","year":"2012","journal-title":"Nat Genet"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/dds359","article-title":"Immunochip analyses identify a novel risk locus for primary biliary cirrhosis at 13q14, multiple independent associations at four established risk loci and epistasis between 1p31 and 7q32 risk variants","volume":"21","author":"Juran","year":"2012","journal-title":"Hum Mol Genet"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1038\/ng.789","article-title":"Genome-wide association study identifies 12 new susceptibility loci for primary biliary cirrhosis","volume":"43","author":"Mells","year":"2011","journal-title":"Nat Genet"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1038\/ng.627","article-title":"Genome-wide meta-analyses identify three loci associated with primary biliary cirrhosis","volume":"42","author":"Liu","year":"2010","journal-title":"Nat Genet"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1038\/ng.631","article-title":"Variants at IRF5-TNPO3, 17q12\u201321 and MMEL1 are associated with primary biliary cirrhosis","volume":"42","author":"Hirschfield","year":"2010","journal-title":"Nat Genet"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1097\/HEP.0000000000000894","article-title":"A genome-wide association study identified PTPN2 as a population-specific susceptibility gene locus for primary biliary cholangitis","volume":"80","author":"Hitomi","year":"2024","journal-title":"Hepatology"},{"key":"B38","doi-asserted-by":"publisher","first-page":"102","DOI":"10.1038\/s41598-018-36490-1","article-title":"POGLUT1, the putative effector gene driven by rs2293370 in primary biliary cholangitis susceptibility locus chromosome 3q13.33","volume":"9","author":"Hitomi","year":"2019","journal-title":"Sci Rep"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddw406","article-title":"Genome-wide association studies identify PRKCB as a novel genetic susceptibility locus for primary biliary cholangitis in the Japanese population","volume":"26","author":"Kawashima","year":"2017","journal-title":"Hum Mol Genet"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2012.08.010","article-title":"Genome-wide association study identifies TNFSF15 and POU2AF1 as susceptibility loci for primary biliary cirrhosis in the Japanese population","volume":"91","author":"Nakamura","year":"2012","journal-title":"Am J Hum Genet"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1038\/gene.2012.17","article-title":"Classical HLA-DRB1 and DPB1 alleles account for HLA associations with primary biliary cirrhosis","volume":"13","author":"Invernizzi","year":"2012","journal-title":"Genes Immun"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2108672119","article-title":"Identification of genetic risk loci and prioritization of genes and pathways for myasthenia gravis: a genome-wide association study","volume":"119","author":"Chia","year":"2022","journal-title":"Proc Natl Acad Sci U.S.A"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2019.09.041","article-title":"HLA-DQA1*05 carriage associated with development of anti-drug antibodies to infliximab and adalimumab in patients with crohn\u2019s disease","volume":"158","author":"Sazonovs","year":"2020","journal-title":"Gastroenterology"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1002\/hep.32417","article-title":"Genome-wide meta-analysis identifies susceptibility loci for autoimmune hepatitis type 1","volume":"76","author":"Li","year":"2022","journal-title":"Hepatology"},{"key":"B45","doi-asserted-by":"publisher","first-page":"494","DOI":"10.1111\/j.1872-034X.2010.00631.x","article-title":"Analysis of HLA-DRB1 polymorphisms in Japanese patients with primary biliary cirrhosis (PBC): The HLA-DRB1polymorphism determines the relative risk of antinuclear antibodies for disease progression in PBC","volume":"40","author":"Nakamura","year":"2010","journal-title":"Hepatol Res"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1202445","article-title":"Differential binding of pyruvate dehydrogenase complex-E2 epitopes by DRB1*08:01 and DRB1*11:01 Is predicted by their structural motifs and correlates with disease risk","volume":"190","author":"Chow","year":"2013","journal-title":"J Immunol"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.1007647","article-title":"The double-sided of human leukocyte antigen-G molecules in type 1 autoimmune hepatitis","volume":"13","author":"Littera","year":"2022","journal-title":"Front Immunol"},{"key":"B48","doi-asserted-by":"publisher","first-page":"e00032","DOI":"10.14309\/ctg.0000000000000032","article-title":"Novel HLA class I alleles outside the extended DR3 haplotype are protective against autoimmune hepatitis","volume":"10","author":"Lammert","year":"2019","journal-title":"Clin Transl Gastroenterol"},{"key":"B49","article-title":"Genetic distinctions between types 1 and 2 autoimmune hepatitis","volume":"92","author":"Czaja","year":"1997","journal-title":"Am J Gastroenterol"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.1038\/ng.2616","article-title":"Dense genotyping of immune-related disease regions identifies nine new risk loci for primary sclerosing cholangitis","volume":"45","author":"Liu","year":"2013","journal-title":"Nat Genet"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.1016\/j.humimm.2008.06.006","article-title":"Association of a TRAF1 and a STAT4 gene polymorphism with increased risk for rheumatoid arthritis in a genetically homogeneous population","volume":"69","author":"Zervou","year":"2008","journal-title":"Hum Immunol"},{"key":"B52","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0142683","article-title":"The Minor Allele of rs7574865 in the STAT4 Gene Is Associated with Increased mRNA and Protein Expression","volume":"10","author":"Lamana","year":"2015","journal-title":"PloS One"},{"key":"B53","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1111\/1756-185X.12363","article-title":"Rs7574865 polymorphism in signal transducers and activators of transcription 4 gene and rheumatoid arthritis: an updated meta-analysis of 28 case-control comparisons","volume":"18","author":"Gu","year":"2015","journal-title":"Int J Rheum Dis"},{"key":"B54","doi-asserted-by":"publisher","DOI":"10.1016\/j.clinre.2015.04.002","article-title":"Association of STAT4 rs7574865 polymorphism with susceptibility to inflammatory bowel disease: A systematic review and meta-analysis","volume":"39","author":"Liu","year":"2015","journal-title":"Clin Res Hepatol Gastroenterol"},{"key":"B55","doi-asserted-by":"publisher","DOI":"10.1097\/CJI.0b013e31817fd8f3","article-title":"Influence of cytotoxic T lymphocyte-associated antigen 4 (CTLA4) common polymorphisms on outcome in treatment of melanoma patients with CTLA-4 blockade","volume":"31","author":"Breunis","year":"2008","journal-title":"J Immunother"},{"key":"B56","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M206894200","article-title":"A common autoimmunity predisposing signal peptide variant of the cytotoxic T-lymphocyte antigen 4 results in inefficient glycosylation of the susceptibility allele","volume":"277","author":"Anjos","year":"2002","journal-title":"J Biol Chem"},{"key":"B57","doi-asserted-by":"publisher","DOI":"10.1038\/sj.gene.6363752","article-title":"CTLA-4 gene expression is influenced by promoter and exon 1 polymorphisms","volume":"2","author":"Ligers","year":"2001","journal-title":"Genes Immun"},{"key":"B58","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2008.06.077","article-title":"Primary biliary cirrhosis is associated with a genetic variant in the 3\u2019 flanking region of the CTLA4 gene","volume":"135","author":"Juran","year":"2008","journal-title":"Gastroenterology"},{"key":"B59","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2014.00206","article-title":"Opportunistic autoimmune disorders potentiated by immune-checkpoint inhibitors anti-CTLA-4 and anti-PD-1","volume":"5","author":"Kong","year":"2014","journal-title":"Front Immunol"},{"key":"B60","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2012.41.6750","article-title":"Management of immune-related adverse events and kinetics of response with ipilimumab","volume":"30","author":"Weber","year":"2012","journal-title":"J Clin Oncol"},{"key":"B61","doi-asserted-by":"publisher","first-page":"42","DOI":"10.1016\/j.jaut.2015.07.004","article-title":"The immunogenetics of primary biliary cirrhosis: A comprehensive review","volume":"64","author":"Webb","year":"2015","journal-title":"J Autoimmun"},{"key":"B62","doi-asserted-by":"publisher","DOI":"10.1155\/2021\/5557814","article-title":"Clinical characteristics and prognosis of concomitant primary biliary cholangitis and autoimmune diseases: A retrospective study","volume":"2021","author":"Liu","year":"2021","journal-title":"Can J Gastroenterol Hepatol"},{"key":"B63","doi-asserted-by":"publisher","DOI":"10.3389\/fgene.2021.791778","article-title":"The causal effects of primary biliary cholangitis on thyroid dysfunction: A two-sample mendelian randomization study","volume":"12","author":"Huang","year":"2021","journal-title":"Front Genet"},{"key":"B64","doi-asserted-by":"publisher","DOI":"10.1038\/s10038-023-01146-0","article-title":"Hematologic traits and primary biliary cholangitis: a Mendelian randomization study","volume":"68","author":"Ke","year":"2023","journal-title":"J Hum Genet"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2025.1600364\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,8,29]],"date-time":"2025-08-29T05:45:18Z","timestamp":1756446318000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2025.1600364\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,8,29]]},"references-count":64,"alternative-id":["10.3389\/fimmu.2025.1600364"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2025.1600364","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,8,29]]},"article-number":"1600364"}}