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DMD is an X-linked recessive disorder involving progressive muscle tissue loss with replacement by fat and fibrotic tissue, leading in most cases to loss of ambulation (LOA) by early to mid-adolescence. The standard pharmacologic treatment is corticosteroid administration, which increases average LOA by 2\u20133 years. There is variation in LOA due to specific\n                    <jats:italic>DMD<\/jats:italic>\n                    mutations, some of which permit the production of residual or partial dystrophin protein and lead to milder phenotypes. But there is also believed to be variation due to genetic modifiers acting even in patients whose\n                    <jats:italic>DMD<\/jats:italic>\n                    mutations preclude dystrophin production altogether, based in part on animal models, and several genes have been implicated as potential modifiers of LOA in DMD patients. Here we consider whether the mechanism of action of any of these genes might be to influence LOA by modifying the effects of corticosteroid exposure. We develop and evaluate a novel statistic, the PPI\n                    <jats:sub>GxE<\/jats:sub>\n                    ; we consider the issue of potential \u201cphenocopies,\u201d or individuals whose late LOA might be due to residual dystrophin production; and we apply our approach to 12 candidate SNPs using our DMD dataset. We find evidence of genotype x steroid interaction effects for 4 out of the 12 SNPs we tested, which can be linked to the TGF-\u03b2 pathway. These results corroborate the hypothesis that modifiers in the TGF-\u03b2 pathway affect LOA by modulating the efficacy of corticosteroid administration.\n                  <\/jats:p>","DOI":"10.1038\/s41431-026-02110-0","type":"journal-article","created":{"date-parts":[[2026,4,20]],"date-time":"2026-04-20T15:23:02Z","timestamp":1776698582000},"page":"964-971","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Gene x environment interaction analysis confirms genetic modifier effects on steroid efficacy via TGF-\u03b2 pathway in Duchenne muscular dystrophy"],"prefix":"10.1038","volume":"34","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3004-3840","authenticated-orcid":false,"given":"Veronica J.","family":"Vieland","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sang-Cheol","family":"Seok","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Megan A.","family":"Waldrop","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leigh M.","family":"Gabel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diane M.","family":"Dunn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6440-3376","authenticated-orcid":false,"given":"Kevin M.","family":"Flanigan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert B.","family":"Weiss","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,4,20]]},"reference":[{"key":"2110_CR1","doi-asserted-by":"publisher","first-page":"304","DOI":"10.1002\/ana.23528","volume":"71","author":"JR Mendell","year":"2012","unstructured":"Mendell JR, Shilling C, Leslie ND, Flanigan KM, al-Dahhak R, Gastier-Foster J, et al. Evidence-based path to newborn screening for Duchenne muscular dystrophy. Ann Neurol. 2012;71:304\u201313.","journal-title":"Ann Neurol"},{"key":"2110_CR2","doi-asserted-by":"publisher","first-page":"1049","DOI":"10.1038\/ejhg.2012.301","volume":"21","author":"SJ Moat","year":"2013","unstructured":"Moat SJ, Bradley DM, Salmon R, Clarke A, Hartley L. Newborn bloodspot screening for Duchenne muscular dystrophy: 21 years experience in Wales (UK). Eur J Hum Genet. 2013;21:1049\u201353.","journal-title":"Eur J Hum Genet"},{"key":"2110_CR3","doi-asserted-by":"publisher","first-page":"280","DOI":"10.1002\/ana.25951","volume":"89","author":"Y de Feraudy","year":"2021","unstructured":"de Feraudy Y, Ben Yaou R, Wahbi K, Stalens C, Stantzou A, Laugel V, et al. Very low residual dystrophin quantity is associated with milder dystrophinopathy. 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Am J Pathol. 2018;188:1263\u201375.","journal-title":"Am J Pathol"}],"container-title":["European Journal of Human Genetics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41431-026-02110-0.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41431-026-02110-0","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41431-026-02110-0.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,7]],"date-time":"2026-07-07T08:41:46Z","timestamp":1783413706000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41431-026-02110-0"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,4,20]]},"references-count":20,"journal-issue":{"issue":"7","published-print":{"date-parts":[[2026,7]]}},"alternative-id":["2110"],"URL":"https:\/\/doi.org\/10.1038\/s41431-026-02110-0","relation":{},"ISSN":["1018-4813","1476-5438"],"issn-type":[{"value":"1018-4813","type":"print"},{"value":"1476-5438","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,4,20]]},"assertion":[{"value":"23 September 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"11 March 2026","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"7 April 2026","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"20 April 2026","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}},{"value":"The research involving human subjects has been performed in accordance with the Declaration of Helsinki and was approved by the Nationwide Children\u2019s Hospital Institutional Review Board (IRB) under approval 0502HSE046. Informed consent was obtained from all subjects.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethical approval"}}]}}