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We collected pulmonary function testing (PFT) data from a large retrospective cohort followed at Centers collaborating in the Italian DMD Network. Furthermore, we analyzed PFT associations with different <jats:italic>DMD<\/jats:italic> mutation types, and with genetic variants in <jats:italic>SPP1<\/jats:italic>, <jats:italic>LTBP4<\/jats:italic>, <jats:italic>CD40<\/jats:italic>, and <jats:italic>ACTN3<\/jats:italic>, known to modify skeletal muscle weakness in DMD. Genetic association findings were independently validated in the Cooperative International Neuromuscular Research Group Duchenne Natural History Study (CINRG\u2010DNHS).<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods and Results<\/jats:title><jats:p>Generalized estimating equation analysis of 1852 PFTs from 327 Italian DMD patients, over an average follow\u2010up time of 4.5\u00a0years, estimated that forced vital capacity (FVC) declined yearly by \u22124.2%, forced expiratory volume in 1\u00a0sec by \u22125.0%, and peak expiratory flow (PEF) by \u22122.9%. Glucocorticoid (GC) treatment was associated with higher values of all PFT measures (approximately\u00a0+\u00a015% across disease stages). Mutations situated 3\u2019 of <jats:italic>DMD<\/jats:italic> intron 44, thus predicted to alter the expression of short dystrophin isoforms, were associated with lower (approximately \u22126%) PFT values, a finding independently validated in the CINRG\u2010DNHS. Deletions amenable to skipping of exon 51 and 53 were independently associated with worse PFT outcomes. A meta\u2010analysis of the two cohorts identified detrimental effects of <jats:italic>SPP1<\/jats:italic> rs28357094 and <jats:italic>CD40<\/jats:italic> rs1883832 minor alleles on both FVC and PEF.<\/jats:p><\/jats:sec><jats:sec><jats:title>Interpretation<\/jats:title><jats:p>These findings support GC efficacy in delaying respiratory insufficiency, and will be useful for the design and interpretation of clinical trials focused on respiratory endpoints in DMD.<\/jats:p><\/jats:sec>","DOI":"10.1002\/acn3.51046","type":"journal-article","created":{"date-parts":[[2020,4,28]],"date-time":"2020-04-28T10:44:32Z","timestamp":1588070672000},"page":"786-798","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":40,"title":["Genetic modifiers of respiratory function in Duchenne muscular dystrophy"],"prefix":"10.1002","volume":"7","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3075-6525","authenticated-orcid":false,"given":"Luca","family":"Bello","sequence":"first","affiliation":[{"name":"Department of Neurosciences DNS University of Padova Padova Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Grazia","family":"D\u2019Angelo","sequence":"additional","affiliation":[{"name":"NeuroMuscular Unit Scientific Institute IRCCS E. 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