{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,12]],"date-time":"2026-06-12T21:24:10Z","timestamp":1781299450700,"version":"3.54.1"},"reference-count":48,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2022,8,4]],"date-time":"2022-08-04T00:00:00Z","timestamp":1659571200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Background: Clinical course variability in Duchenne muscular dystrophy (DMD) is partially explained by the mutation location in the DMD gene and variants in modifier genes. We assessed the effect of the SPP1, CD40, and LTBP4 genes and DMD mutation location on loss of ambulation (LoA). Methods: SNPs in SPP1-rs28357094, LTBP4-rs2303729, rs1131620, rs1051303, rs10880, and CD40-rs1883832 were genotyped, and their effect was assessed by survival and hierarchical cluster analysis. Results: Patients on glucocorticoid corticosteroid (GC) therapy experienced LoA one year later (p = 0.04). The modifying effect of SPP1 and CD40 variants, as well as LTBP4 haplotypes, was not observed using a log-rank test and multivariant Cox regression analysis. Cluster analysis revealed two subgroups with statistical trends in differences in age at LoA. Almost all patients in the cluster with later LoA had the protective IAAM LTBP4 haplotype and statistically significantly fewer CD40 genotypes with harmful T allele and \u201cdistal\u201d DMD mutations. Conclusions: The modifying effect of SPP1, CD40, and LTBP4 was not replicated in Serbian patients, although our cohort was comparable in terms of its DMD mutation type distribution, SNP allele frequencies, and GC-positive effect with other European cohorts. Cluster analysis may be able to identify patient subgroups carrying a combination of the genetic variants that modify LoA.<\/jats:p>","DOI":"10.3390\/genes13081385","type":"journal-article","created":{"date-parts":[[2022,8,4]],"date-time":"2022-08-04T02:07:22Z","timestamp":1659578842000},"page":"1385","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["LTBP4, SPP1, and CD40 Variants: Genetic Modifiers of Duchenne Muscular Dystrophy Analyzed in Serbian Patients"],"prefix":"10.3390","volume":"13","author":[{"given":"Ana","family":"Kosac","sequence":"first","affiliation":[{"name":"Department of Neurology, Clinic of Neurology and Psychiatry for Children and Youth, 11000 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jovan","family":"Pesovic","sequence":"additional","affiliation":[{"name":"Centre for Human Molecular Genetics, Faculty of Biology, University of Belgrade, 11000 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lana","family":"Radenkovic","sequence":"additional","affiliation":[{"name":"Centre for Human Molecular Genetics, Faculty of Biology, University of Belgrade, 11000 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4316-9231","authenticated-orcid":false,"given":"Milos","family":"Brkusanin","sequence":"additional","affiliation":[{"name":"Centre for Human Molecular Genetics, Faculty of Biology, University of Belgrade, 11000 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nemanja","family":"Radovanovic","sequence":"additional","affiliation":[{"name":"Centre for Human Molecular Genetics, Faculty of Biology, University of Belgrade, 11000 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marina","family":"Djurisic","sequence":"additional","affiliation":[{"name":"Laboratory of Medical Genetics, Mother and Child Health Care Institute of Serbia \u201cDr Vukan Cupic\u201d, 11000 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0334-3896","authenticated-orcid":false,"given":"Danijela","family":"Radivojevic","sequence":"additional","affiliation":[{"name":"Laboratory of Medical Genetics, Mother and Child Health Care Institute of Serbia \u201cDr Vukan Cupic\u201d, 11000 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jelena","family":"Mladenovic","sequence":"additional","affiliation":[{"name":"Department of Neurology, Clinic of Neurology and Psychiatry for Children and Youth, 11000 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8979-0445","authenticated-orcid":false,"given":"Slavica","family":"Ostojic","sequence":"additional","affiliation":[{"name":"Department of Neurology, Mother and Child Health Care Institute of Serbia \u201cDr Vukan Cupic\u201d, 11000 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gordana","family":"Kovacevic","sequence":"additional","affiliation":[{"name":"Department of Neurology, Mother and Child Health Care Institute of Serbia \u201cDr Vukan Cupic\u201d, 11000 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruzica","family":"Kravljanac","sequence":"additional","affiliation":[{"name":"Department of Neurology, Mother and Child Health Care Institute of Serbia \u201cDr Vukan Cupic\u201d, 11000 Belgrade, Serbia"},{"name":"Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2079-4077","authenticated-orcid":false,"given":"Dusanka","family":"Savic Pavicevic","sequence":"additional","affiliation":[{"name":"Centre for Human Molecular Genetics, Faculty of Biology, University of Belgrade, 11000 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vedrana","family":"Milic Rasic","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,8,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"687","DOI":"10.1016\/S0140-6736(02)07815-7","article-title":"The muscular dystrophies","volume":"359","author":"Emery","year":"2002","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1017\/S0012162206000351","article-title":"Treatment of the heart in Duchenne muscular dystrophy","volume":"48","author":"Baxter","year":"2006","journal-title":"Dev. 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