Corticosteroid effects on blood gene expression in Duchenne muscular dystrophy

Abstract

Though Deflazacort and prednisone improve clinical endpoints in Duchenne muscular dystrophy (DMD) patients, Deflazacort produces fewer side effects. As mechanisms of improvement and side effect differences remain unknown, we evaluated effects of corticosteroid administration on gene expression in blood of DMD patients. Whole blood was obtained from 14 children and adolescents with DMD treated with corticosteroids (DMD-STEROID) and 20 DMD children and adolescents naïve to corticosteroids (DMD). The DMD-STEROID group was further subdivided into Deflazacort and prednisone groups. Affymetrix U133 Plus 2.0 expression microarrays were used to evaluate mRNA expression. Expression of 524 probes changed with corticosteroids, including genes in iron trafficking and the chondroitin sulfate biosynthesis pathway. Deflazacort compared with prednisone yielded 508 regulated probes, including many involved in adipose metabolism. These genes and pathways help explain mechanisms of efficacy and side effects of corticosteroids, and could provide new treatment targets for DMD and other neuromuscular disorders.

Systemic Steroid Exposure Is Associated with Differential Methylation in Chronic Obstructive Pulmonary Disease

“…Forty transcripts (in 36 unique genes) overlapped with our loci (Table E14); 29 of these transcripts (in 25 unique genes) demonstrated an anticorrelated direction of effect. In contrast to the acute exposure studied by Menke and colleagues (8), Lit and colleagues examined differential expression in children and adolescents with Duchenne's muscular dystrophy exposed to chronic glucocorticoids (64). Of the 524 differentially expressed probes reported, 40 transcripts (in 31 unique genes) were annotated to genes that overlap with our differentially methylated sites (Table E15); 36 of the transcripts (in 28 unique genes) demonstrated an anticorrelated direction of effect relative to the changes in methylation in our cohort.…”

Comparing Deflazacort and Prednisone in Duchenne Muscular Dystrophy

“…In dystrophic muscle, the expression of genes important for myogenesis, muscle regeneration and muscle maturation was increased towards normal ranges by deflazacort treatment, while expression of several genes with roles in inflammation was reduced towards normal ranges [11]. In a second study that compared gene expression in whole blood from 14 corticosteroid-treated children and adolescents with DMD with 20 who were corticosteroid-naïve, treatment with corticosteroids was found to upregulate genes associated with primary and secondary granules in neutrophils, iron trafficking, and chondroitin sulfate synthesis [12]. When comparing gene expression in deflazacort-and prednisone-treated individuals, there were fewer expression changes overall with deflazacort versus prednisone.…”

“…ences between the treatments centered on genes involved in adipose metabolism, potentially suggesting mechanisms by which corticosteroid-related weight gain, more typically associated with prednisone/prednisolone than with deflazacort, may be orchestrated [12].…”

Genome response to tissue plasminogen activator in experimental ischemic stroke

“…The rationale for gene expression changes in the blood following ischemic stroke is largely based on the immune response to ischemic brain that is distinct from other neurological conditions [11,12]. Gene expression is also affected by medications, as observed with aspirin in ischemic stroke and corticosteroids in Duchenne muscular dystrophy [8,13]. …”