{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,24]],"date-time":"2026-01-24T18:41:24Z","timestamp":1769280084925,"version":"3.49.0"},"reference-count":42,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2026,1,22]],"date-time":"2026-01-22T00:00:00Z","timestamp":1769040000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Juvenile scleroderma (JS), comprising localized (JLSd) and systemic (JSSc) forms, is a rare autoimmune disorder. This study investigated associations of polymorphisms in extracellular matrix (MMP1, MMP9) and vascular homeostasis (NOS3) genes with JS risk and immunological phenotypes. A case\u2013control study involved 215JS patients (194 JLSd, 21 JSSc) and 72 controls. SNPs (MMP1 rs1799750, MMP9 rs3918242, NOS3 rs1799983) were genotyped using real-time PCR followed by minisequencing and mass spectrometric analysis of reaction products. Associations with disease risk, subtypes, and immunological markers were analyzed statistically. The MMP9 (rs3918242) CT genotype was significantly associated with JLSd (OR = 2.23, 95% CI: 1.14\u20134.37, p = 0.022), showing a trend in linear facial forms. The NOS3 (rs1799983) GG genotype demonstrated a trend toward association with JSSc (OR = 2.61, 95% CI: 0.92\u20137.37, p = 0.065). No significant associations were found for rs1799750 MMP1 and risk of disease development. The MMP9 risk genotype did not correlate with scleroderma-specific autoantibodies, while the NOS3 GG genotype was associated with lower serum levels of anti-collagen IV antibodies (p = 0.039). Genetic associations differ for JS subtypes: MMP9 with JLSd and NOS3 with JSSc. Children with CT polymorphism MMP9 (rs3918242) and with NOS3 (rs1799983) GG genotype were found to be genetically predisposed for the development of JS.<\/jats:p>","DOI":"10.3390\/ijms27021109","type":"journal-article","created":{"date-parts":[[2026,1,23]],"date-time":"2026-01-23T09:16:59Z","timestamp":1769159819000},"page":"1109","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Association of MMP9 and NOS3 Polymorphisms with Distinct Clinical Forms of Juvenile Scleroderma and Characteristics of Humoral Immunity"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3537-5390","authenticated-orcid":false,"given":"Maria","family":"Osminina","sequence":"first","affiliation":[{"name":"Department of Children\u2019s Diseases, Sechenov First Moscow State Medical University, 119435 Moscow, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0701-5956","authenticated-orcid":false,"given":"Vera","family":"Podzolkova","sequence":"additional","affiliation":[{"name":"Department of Children\u2019s Diseases, Sechenov First Moscow State Medical University, 119435 Moscow, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1863-3768","authenticated-orcid":false,"given":"Maria","family":"Litvinova","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics and Postgenomic Technologies, Sechenov First Moscow State Medical University, 119435 Moscow, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0547-3686","authenticated-orcid":false,"given":"Natalia","family":"Geppe","sequence":"additional","affiliation":[{"name":"Department of Children\u2019s Diseases, Sechenov First Moscow State Medical University, 119435 Moscow, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Svetlana","family":"Chebysheva","sequence":"additional","affiliation":[{"name":"Department of Children\u2019s Diseases, Sechenov First Moscow State Medical University, 119435 Moscow, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2125-569X","authenticated-orcid":false,"given":"Lusine","family":"Khachatryan","sequence":"additional","affiliation":[{"name":"Department of Children\u2019s Diseases, Sechenov First Moscow State Medical University, 119435 Moscow, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0813-1155","authenticated-orcid":false,"given":"Natalia","family":"Golovanova","sequence":"additional","affiliation":[{"name":"Department of Children\u2019s Diseases, Sechenov First Moscow State Medical University, 119435 Moscow, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6389-5177","authenticated-orcid":false,"given":"Yulia","family":"Kostina","sequence":"additional","affiliation":[{"name":"Clinic of Children\u2019s Diseases, Sechenov\u2019s Center of Maternity and Childhood, 119435 Moscow, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Oksana","family":"Lazareva-Batyreva","sequence":"additional","affiliation":[{"name":"Clinic of Children\u2019s Diseases, Sechenov\u2019s Center of Maternity and Childhood, 119435 Moscow, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4125-0335","authenticated-orcid":false,"given":"Angelina","family":"Polyanskaya","sequence":"additional","affiliation":[{"name":"Department of Children\u2019s Diseases, Sechenov First Moscow State Medical University, 119435 Moscow, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8132-0169","authenticated-orcid":false,"given":"Olga","family":"Shpitonkova","sequence":"additional","affiliation":[{"name":"Department of Children\u2019s Diseases, Sechenov First Moscow State Medical University, 119435 Moscow, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-5444-2797","authenticated-orcid":false,"given":"Tatiana","family":"Subbotina","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics and Postgenomic Technologies, Sechenov First Moscow State Medical University, 119435 Moscow, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tigran","family":"Areian","sequence":"additional","affiliation":[{"name":"N.V. Sklifosovsky Institute of Clinical Medicine, Sechenov First Moscow State Medical University, 119048 Moscow, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7498-1636","authenticated-orcid":false,"given":"Nadezhda","family":"Podchernyaeva","sequence":"additional","affiliation":[{"name":"Department of Children\u2019s Diseases, Sechenov First Moscow State Medical University, 119435 Moscow, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,1,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"89","DOI":"10.20953\/1817-7646-2025-3-89-97","article-title":"Clinical and Immunological Manifestations of Systemic Scleroderma in Children According to Data from a Rheumatology Center","volume":"20","author":"Osminina","year":"2025","journal-title":"Vopr. Prakt. Pediatr."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"561","DOI":"10.1097\/BOR.0000000000000331","article-title":"Animal Models of Scleroderma: Recent Progress","volume":"28","author":"Marangoni","year":"2016","journal-title":"Curr. Opin. Rheumatol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1007\/978-3-030-92616-8_7","article-title":"The Immunogenetics of Morphea and Lichen Sclerosus","volume":"Volume 1367","author":"Rezaei","year":"2022","journal-title":"The Immunogenetics of Dermatologic Diseases"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"174","DOI":"10.1038\/s41584-024-01217-2","article-title":"An International Perspective on the Future of Systemic Sclerosis Research","volume":"21","author":"Abraham","year":"2025","journal-title":"Nat. Rev. Rheumatol."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Allanore, Y., Varga, J., Denton, C.P., Kuwana, M., Chung, L., and Shah, A.A. (2024). Scleroderma: From Pathogenesis to Comprehensive Management, Springer International Publishing.","DOI":"10.1007\/978-3-031-40658-4"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1725","DOI":"10.1002\/1529-0131(199810)41:10<1725::AID-ART4>3.0.CO;2-N","article-title":"Oklahoma Choctaw and Systemic Sclerosis: The Founder Effect and Genetic Susceptibility","volume":"41","author":"Harley","year":"1998","journal-title":"Arthritis Rheumatol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"552","DOI":"10.1073\/pnas.1906593116","article-title":"HLA and Autoantibodies Define Scleroderma Subtypes and Risk in African and European Americans and Suggest a Role for Molecular Mimicry","volume":"117","author":"Gourh","year":"2020","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"He, D., Wang, J., Yi, L., Guo, X., Guo, S., Guo, G., Tu, W., Wu, W., Yang, L., and Xiao, R. (2014). Association of the HLA-DRB1 with Scleroderma in Chinese Population. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0106939"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"563","DOI":"10.1111\/tan.14793","article-title":"Association of HLA-DRB1*15:02:01, DQB1*05:01:24 and DPB1*13:01:01 in Thai Patients with Systemic Sclerosis","volume":"100","author":"Louthrenoo","year":"2022","journal-title":"HLA"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"3170","DOI":"10.1002\/art.38814","article-title":"Major Histocompatibility Complex Class I and Class II Alleles May Confer Susceptibility to or Protection Against Morphea: Findings from the Morphea in Adults and Children Cohort","volume":"66","author":"Jacobe","year":"2014","journal-title":"Arthritis Rheumatol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1136\/annrheumdis-2019-215894","article-title":"Global Skin Gene Expression Analysis of Early Diffuse Cutaneous Systemic Sclerosis Shows a Prominent Innate and Adaptive Inflammatory Profile","volume":"79","author":"Skaug","year":"2020","journal-title":"Ann. Rheum. Dis."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Gumkowska-Sroka, O., Kotyla, K., and Kotyla, P. (2024). Immunogenetics of Systemic Sclerosis. Genes, 15.","DOI":"10.3390\/genes15050586"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1002\/art.24183","article-title":"Association Between the IRF5 Rs2004640 Functional Polymorphism and Systemic Sclerosis: A New Perspective for Pulmonary Fibrosis","volume":"60","author":"Guedj","year":"2009","journal-title":"Arthritis Rheumatol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"408","DOI":"10.1111\/ijd.12839","article-title":"Polymorphisms in STAT 4 and IRF 5 Increase the Risk of Systemic Sclerosis: A Meta-analysis","volume":"55","author":"Xu","year":"2016","journal-title":"Int. J. Dermatol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"926","DOI":"10.1093\/hmg\/dds099","article-title":"A GWAS Follow-up Study Reveals the Association of the IL12RB2 Gene with Systemic Sclerosis in Caucasian Populations","volume":"21","author":"Martin","year":"2012","journal-title":"Hum. Mol. Genet."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"3521","DOI":"10.1002\/art.38870","article-title":"Identification of IL12RB1 as a Novel Systemic Sclerosis Susceptibility Locus","volume":"66","author":"Guerra","year":"2014","journal-title":"Arthritis Rheumatol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"602","DOI":"10.1136\/annrheumdis-2012-201888","article-title":"Confirmation of TNIP1 but Not RHOB and PSORS1C1 as Systemic Sclerosis Risk Factors in a Large Independent Replication Study","volume":"72","author":"Martin","year":"2013","journal-title":"Ann. Rheum. Dis."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"192","DOI":"10.1177\/2397198320913695","article-title":"Genetics of Systemic Sclerosis","volume":"5","author":"Ishikawa","year":"2020","journal-title":"J. Scleroderma Relat. Disord."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"599","DOI":"10.3899\/jrheum.090973","article-title":"Association of Metalloproteinase Gene Polymorphisms with Systemic Sclerosis in the European Caucasian Population","volume":"37","author":"Wipff","year":"2010","journal-title":"J. Rheumatol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"873","DOI":"10.3892\/ijmm.2011.661","article-title":"Analysis of Matrix Metalloproteinase-9 Gene Polymorphism-1562 C\/T in Patients Suffering from Systemic Sclerosis with and Without Ulcers","volume":"27","author":"Skarmoutsou","year":"2011","journal-title":"Int. J. Mol. Med."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"15049077","DOI":"10.4238\/gmr15049077","article-title":"Matrix Metalloproteinase Gene Polymorphisms and Susceptibility to Systemic Sclerosis","volume":"15","author":"Rech","year":"2016","journal-title":"Genet. Mol. Res."},{"key":"ref_22","first-page":"169","article-title":"Endothelial Nitric Oxide Gene Polymorphism and Risk of Systemic Sclerosis: Predisposition Effect of T-786C Promoter and Protective Effect of 27 Bp Repeats in Intron 4","volume":"28","author":"Sinici","year":"2010","journal-title":"Clin. Exp. Rheumatol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"2263","DOI":"10.1002\/art.21933","article-title":"Hemorheologic Profile in Systemic Sclerosis: Role of NOS3\u2212786T>C and 894G>T Polymorphisms in Modulating Both the Hemorheologic Parameters and the Susceptibility to the Disease","volume":"54","author":"Fatini","year":"2006","journal-title":"Arthritis Rheumatol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"540","DOI":"10.1016\/S0002-9343(02)01069-0","article-title":"High Prevalence of Polymorphisms of Angiotensin-Converting Enzyme (I\/D) and Endothelial Nitric Oxide Synthase (Glu298Asp) in Patients with Systemic Sclerosis","volume":"112","author":"Fatini","year":"2002","journal-title":"Am. J. Med."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1177\/1358836X0000500304","article-title":"Differential Expression of Nitric Oxide by Dermal Microvascular Endothelial Cells from Patients with Scleroderma","volume":"5","author":"Romero","year":"2000","journal-title":"Vasc. Med."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"e1874205X2112241","DOI":"10.2174\/1874205X-v16-e2112241","article-title":"Involvement of the Nervous System in Systemic Sclerosis","volume":"16","author":"Polunosika","year":"2022","journal-title":"Open Neurol. J."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"e175","DOI":"10.1016\/S2665-9913(20)30385-4","article-title":"Circulating Collagen Neo-Epitopes and Their Role in the Prediction of Fibrosis in Patients with Systemic Sclerosis: A Multicentre Cohort Study","volume":"3","author":"Dobrota","year":"2021","journal-title":"Lancet Rheumatol."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Juhl, P., Bay-Jensen, A.-C., Karsdal, M., Siebuhr, A.S., Franchimont, N., and Chavez, J. (2018). Serum Biomarkers of Collagen Turnover as Potential Diagnostic Tools in Diffuse Systemic Sclerosis: A Cross-Sectional Study. PLoS ONE, 13.","DOI":"10.1371\/journal.pone.0207324"},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Velosa, A.P.P., Brito, L., de Jesus Queiroz, Z.A., Carrasco, S., Tomaz de Miranda, J., Farhat, C., Goldenstein-Schainberg, C., Parra, E.R., de Andrade, D.C.O., and Silva, P.L. (2020). Identification of Autoimmunity to Peptides of Collagen V A1 Chain as Newly Biomarkers of Early Stage of Systemic Sclerosis. Front. Immunol., 11.","DOI":"10.3389\/fimmu.2020.604602"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1177\/2397198319870667","article-title":"Pathogenic Roles of Autoantibodies in Systemic Sclerosis: Current Understandings in Pathogenesis","volume":"5","author":"Hoa","year":"2020","journal-title":"J. Scleroderma Relat. Disord."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"3971","DOI":"10.1002\/art.22207","article-title":"Systemic Sclerosis in Childhood: Clinical and Immunologic Features of 153 Patients in an International Database","volume":"54","author":"Martini","year":"2006","journal-title":"Arthritis Rheumatol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"2422","DOI":"10.3899\/jrheum.100001","article-title":"Characteristics of Patients with Juvenile Onset Systemic Sclerosis in an Adult Single-Center Cohort","volume":"37","author":"Foeldvari","year":"2010","journal-title":"J. Rheumatol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"152197","DOI":"10.1016\/j.semarthrit.2023.152197","article-title":"Juvenile and Adult-Onset Scleroderma: Different Clinical Phenotypes","volume":"60","author":"Adrovic","year":"2023","journal-title":"Semin. Arthritis Rheum."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"e185758","DOI":"10.1172\/jci.insight.185758","article-title":"Unique and Shared Transcriptomic Signatures Underlying Localized Scleroderma Pathogenesis Identified Using Interpretable Machine Learning","volume":"10","author":"Rosen","year":"2025","journal-title":"JCI Insight"},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Werner, G., Sanyal, A., Mirizio, E., Hutchins, T., Tabib, T., Lafyatis, R., Jacobe, H., and Torok, K.S. (2023). Single-Cell Transcriptome Analysis Identifies Subclusters with Inflammatory Fibroblast Responses in Localized Scleroderma. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24129796"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1921","DOI":"10.1002\/art.41758","article-title":"Transcriptomic Evaluation of Juvenile Localized Scleroderma Skin with Histologic and Clinical Correlation","volume":"73","author":"Schutt","year":"2021","journal-title":"Arthritis Rheumatol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"e159566","DOI":"10.1172\/jci.insight.159566","article-title":"Tofacitinib Blocks IFN-Regulated Biomarker Genes in Skin Fibroblasts and Keratinocytes in a Systemic Sclerosis Trial","volume":"7","author":"Khanna","year":"2022","journal-title":"JCI Insight"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1007\/s12016-021-08891-0","article-title":"Therapeutic Approaches to Systemic Sclerosis: Recent Approvals and Future Candidate Therapies","volume":"64","author":"Lescoat","year":"2021","journal-title":"Clinic Rev. Allerg. Immunol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"657","DOI":"10.1038\/s41584-018-0099-0","article-title":"New Insights into the Genetics and Epigenetics of Systemic Sclerosis","volume":"14","author":"Angiolilli","year":"2018","journal-title":"Nat. Rev. Rheumatol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"319","DOI":"10.1038\/s41467-023-44541-z","article-title":"GWAS for Systemic Sclerosis Identifies Six Novel Susceptibility Loci Including One in the Fc\u03b3 Receptor Region","volume":"15","author":"Ishikawa","year":"2024","journal-title":"Nat. Commun."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1002\/art.22551","article-title":"The Pediatric Rheumatology European Society\/American College of Rheumatology\/European League against Rheumatism Provisional Classification Criteria for Juvenile Systemic Sclerosis","volume":"57","author":"Zulian","year":"2007","journal-title":"Arthritis Rheumatol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"606","DOI":"10.1097\/01.bor.0000245727.40630.c3","article-title":"Localized Scleroderma","volume":"18","author":"Laxer","year":"2006","journal-title":"Curr. Opin. Rheumatol."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/2\/1109\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,23]],"date-time":"2026-01-23T09:22:09Z","timestamp":1769160129000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/2\/1109"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,1,22]]},"references-count":42,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2026,1]]}},"alternative-id":["ijms27021109"],"URL":"https:\/\/doi.org\/10.3390\/ijms27021109","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,1,22]]}}}