Genetic modifiers of duchenne muscular dystrophy and dilated cardiomyopathy

Andrea Barp, Luca Bello, Luisa Politano, Paola Melacini, Chiara Calore, Angela Polo, Sara Vianello, Gianni Sorarù, Claudio Semplicini, Boris Pantic, Antonella Taglia, Ester Picillo, Francesca Magri, Ksenija Gorni, Sonia Messina, Gian Luca Vita, Giuseppe Vita, Giacomo P. Comi, Mario Ermani, Vincenzo CalvoCorrado Angelini, Eric P. Hoffman, Elena Pegoraro

Research output: Contribution to journalArticle

21 Citations (Scopus)

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.

Original languageEnglish
Article numbere0141240
JournalPLoS One
Volume10
Issue number10
DOIs
Publication statusPublished - Oct 29 2015

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muscular dystrophy
modifiers (genes)
Duchenne Muscular Dystrophy
cardiomyopathy
Dilated Cardiomyopathy
Polymorphism
Glucocorticoids
Assays
Adrenal Cortex Hormones
Steroids
Age of Onset
protective effect
Alleles
alleles
adrenal cortex hormones
glucocorticoids
Stroke Volume
Haplotypes
drug therapy
Walking

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Barp, A., Bello, L., Politano, L., Melacini, P., Calore, C., Polo, A., ... Pegoraro, E. (2015). Genetic modifiers of duchenne muscular dystrophy and dilated cardiomyopathy. PLoS One, 10(10), [e0141240]. https://doi.org/10.1371/journal.pone.0141240

Genetic modifiers of duchenne muscular dystrophy and dilated cardiomyopathy. / Barp, Andrea; Bello, Luca; Politano, Luisa; Melacini, Paola; Calore, Chiara; Polo, Angela; Vianello, Sara; Sorarù, Gianni; Semplicini, Claudio; Pantic, Boris; Taglia, Antonella; Picillo, Ester; Magri, Francesca; Gorni, Ksenija; Messina, Sonia; Vita, Gian Luca; Vita, Giuseppe; Comi, Giacomo P.; Ermani, Mario; Calvo, Vincenzo; Angelini, Corrado; Hoffman, Eric P.; Pegoraro, Elena.

In: PLoS One, Vol. 10, No. 10, e0141240, 29.10.2015.

Research output: Contribution to journalArticle

Barp, A, Bello, L, Politano, L, Melacini, P, Calore, C, Polo, A, Vianello, S, Sorarù, G, Semplicini, C, Pantic, B, Taglia, A, Picillo, E, Magri, F, Gorni, K, Messina, S, Vita, GL, Vita, G, Comi, GP, Ermani, M, Calvo, V, Angelini, C, Hoffman, EP & Pegoraro, E 2015, 'Genetic modifiers of duchenne muscular dystrophy and dilated cardiomyopathy', PLoS One, vol. 10, no. 10, e0141240. https://doi.org/10.1371/journal.pone.0141240
Barp A, Bello L, Politano L, Melacini P, Calore C, Polo A et al. Genetic modifiers of duchenne muscular dystrophy and dilated cardiomyopathy. PLoS One. 2015 Oct 29;10(10). e0141240. https://doi.org/10.1371/journal.pone.0141240
Barp, Andrea ; Bello, Luca ; Politano, Luisa ; Melacini, Paola ; Calore, Chiara ; Polo, Angela ; Vianello, Sara ; Sorarù, Gianni ; Semplicini, Claudio ; Pantic, Boris ; Taglia, Antonella ; Picillo, Ester ; Magri, Francesca ; Gorni, Ksenija ; Messina, Sonia ; Vita, Gian Luca ; Vita, Giuseppe ; Comi, Giacomo P. ; Ermani, Mario ; Calvo, Vincenzo ; Angelini, Corrado ; Hoffman, Eric P. ; Pegoraro, Elena. / Genetic modifiers of duchenne muscular dystrophy and dilated cardiomyopathy. In: PLoS One. 2015 ; Vol. 10, No. 10.
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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.",
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T1 - Genetic modifiers of duchenne muscular dystrophy and dilated cardiomyopathy

AU - Barp, Andrea

AU - Bello, Luca

AU - Politano, Luisa

AU - Melacini, Paola

AU - Calore, Chiara

AU - Polo, Angela

AU - Vianello, Sara

AU - Sorarù, Gianni

AU - Semplicini, Claudio

AU - Pantic, Boris

AU - Taglia, Antonella

AU - Picillo, Ester

AU - Magri, Francesca

AU - Gorni, Ksenija

AU - Messina, Sonia

AU - Vita, Gian Luca

AU - Vita, Giuseppe

AU - Comi, Giacomo P.

AU - Ermani, Mario

AU - Calvo, Vincenzo

AU - Angelini, Corrado

AU - Hoffman, Eric P.

AU - Pegoraro, Elena

PY - 2015/10/29

Y1 - 2015/10/29

N2 - 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.

AB - 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.

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