title: Genetic Modifiers of Duchenne Muscular Dystrophy and Dilated Cardiomyopathy.
abstract: OBJECTIVE
  Dilated cardiomyopathy (DCM) is a major complication and leading cause of death in Duchenne muscular dystrophy (DMD). DCM onset is variable, suggesting modifier effects of genetic or environmental factors. We aimed to determine if polymorphisms previously associated with age at loss of independent ambulation (LoA) in DMD (rs28357094 in the SPP1 promoter, rs10880 and the VTTT/IAAM haplotype in LTBP4) also modify DCM onset.
  
  
  METHODS
  A multicentric cohort of 178 DMD patients was genotyped by TaqMan assays. We performed a time-to-event analysis of DCM onset, with age as time variable, and finding of left ventricular ejection fraction < 50% and/or end diastolic volume > 70 mL/m2 as event (confirmed by a previous normal exam < 12 months prior); DCM-free patients were censored at the age of last echocardiographic follow-up.
  
  
  RESULTS
  Patients were followed up to an average age of 15.9 ± 6.7 years. Seventy-one/178 patients developed DCM, and median age at onset was 20.0 years. Glucocorticoid corticosteroid treatment (n = 88 untreated; n = 75 treated; n = 15 unknown) did not have a significant independent effect on DCM onset. Cardiological medications were not administered before DCM onset in this population. We observed trends towards a protective effect of the dominant G allele at SPP1 rs28357094 and recessive T allele at LTBP4 rs10880, which was statistically significant in steroid-treated patients for LTBP4 rs10880 (< 50% T/T patients developing DCM during follow-up [n = 13]; median DCM onset 17.6 years for C/C-C/T, log-rank p = 0.027).
  
  
  CONCLUSIONS
  We report a putative protective effect of DMD genetic modifiers on the development of cardiac complications, that might aid in risk stratification if confirmed in independent cohorts.
authors.affiliation: Neuromuscular Center, Department of Neuroscience, University of Padova, Padova, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Barp
authors.affiliation: Neuromuscular Center, Department of Neuroscience, University of Padova, Padova, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Bello
authors.affiliation: Department of Experimental Medicine, Cardiomyology and Medical Genetics, Second University of Naples, Naples, Italy.
authors.forename: Luisa
authors.initials: L
authors.lastname: Politano
authors.affiliation: Department of Cardiac, Thoracic and Vascular Sciences, Cardiology Section, University of Padova, Padova, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Melacini
authors.affiliation: Department of Cardiac, Thoracic and Vascular Sciences, Cardiology Section, University of Padova, Padova, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Calore
authors.affiliation: Department of Cardiac, Thoracic and Vascular Sciences, Cardiology Section, University of Padova, Padova, Italy.
authors.forename: Angela
authors.initials: A
authors.lastname: Polo
authors.affiliation: Neuromuscular Center, Department of Neuroscience, University of Padova, Padova, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Vianello
authors.affiliation: Neuromuscular Center, Department of Neuroscience, University of Padova, Padova, Italy.
authors.forename: Gianni
authors.initials: G
authors.lastname: Sorarù
authors.affiliation: Neuromuscular Center, Department of Neuroscience, University of Padova, Padova, Italy.
authors.forename: Claudio
authors.initials: C
authors.lastname: Semplicini
authors.affiliation: Neuromuscular Center, Department of Neuroscience, University of Padova, Padova, Italy.
authors.forename: Boris
authors.initials: B
authors.lastname: Pantic
authors.affiliation: Department of Experimental Medicine, Cardiomyology and Medical Genetics, Second University of Naples, Naples, Italy.
authors.forename: Antonella
authors.initials: A
authors.lastname: Taglia
authors.affiliation: Department of Experimental Medicine, Cardiomyology and Medical Genetics, Second University of Naples, Naples, Italy.
authors.forename: Ester
authors.initials: E
authors.lastname: Picillo
authors.affiliation: Dino Ferrari Centre, Department of Neurological Sciences, University of Milan, I.R.C.C.S. Foundation Cà Granda, Ospedale Maggiore Policlinico, Milan, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Magri
authors.affiliation: NEuroMuscular Omnicentre (NEMO), Fondazione Serena Onlus, Ospedale Niguarda Cà Granda, Milano, Italy.
authors.forename: Ksenija
authors.initials: K
authors.lastname: Gorni
authors.affiliation: Department of Neurosciences, Psychiatry and Anaesthesiology, University of Messina, Messina, Italy.
authors.forename: Sonia
authors.initials: S
authors.lastname: Messina
authors.affiliation: Department of Neurosciences, Psychiatry and Anaesthesiology, University of Messina, Messina, Italy.
authors.forename: Gian Luca
authors.initials: GL
authors.lastname: Vita
authors.affiliation: Department of Neurosciences, Psychiatry and Anaesthesiology, University of Messina, Messina, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Vita
authors.affiliation: Dino Ferrari Centre, Department of Neurological Sciences, University of Milan, I.R.C.C.S. Foundation Cà Granda, Ospedale Maggiore Policlinico, Milan, Italy.
authors.forename: Giacomo P
authors.initials: GP
authors.lastname: Comi
authors.affiliation: Neuromuscular Center, Department of Neuroscience, University of Padova, Padova, Italy.
authors.forename: Mario
authors.initials: M
authors.lastname: Ermani
authors.affiliation: Department of Philosophy, Sociology, Pedagogy and Applied Psychology (FISPPA), University of Padova, Padova, Italy.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Calvo
authors.affiliation: Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) San Camillo, Venice, Italy.
authors.forename: Corrado
authors.initials: C
authors.lastname: Angelini
authors.affiliation: Research Center for Genetic Medicine, Children's National Medical Center, 111 Michigan Avenue, NW, Washington, DC, 20010, United States of America.
authors.forename: Eric P
authors.initials: EP
authors.lastname: Hoffman
authors.affiliation: Neuromuscular Center, Department of Neuroscience, University of Padova, Padova, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Pegoraro
mesh_terms: D000293:Adolescent; D002311:Cardiomyopathy, Dilated / Q000209:etiology*; D002648:Child; D060045:Genes, Modifier; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D005838:Genotype; D005938:Glucocorticoids / Q000627:therapeutic use; D006801:Humans; D040582:Inheritance Patterns; D053208:Kaplan-Meier Estimate; D053779:Latent TGF-beta Binding Proteins / Q000235:genetics; D020388:Muscular Dystrophy, Duchenne / Q000150:complications* / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality; D053495:Osteopontin / Q000235:genetics; D011379:Prognosis; D055815:Young Adult
chemical_list: D005938:Glucocorticoids; C509040:LTBP4 protein, human; D053779:Latent TGF-beta Binding Proteins; C506895:SPP1 protein, human; D053495:Osteopontin