Genetic Modifiers of Duchenne Muscular Dystrophy and Dilated Cardiomyopathy

<div><p>Objective</p><p>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 <i>SPP1</i> promoter, rs10880 and the VTTT/IAAM haplotype in <i>LTBP4</i>) also modify DCM onset.</p><p>Methods</p><p>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.</p><p>Results</p><p>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 <i>SPP1</i> rs28357094 and recessive T allele at <i>LTBP4</i> rs10880, which was statistically significant in steroid-treated patients for <i>LTBP4</i> 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).</p><p>Conclusions</p><p>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.</p></div

Median age at DCM onset by <i>SPP1</i> and <i>LTBP4</i> genotype.

<p>*Significant difference between genotypes (log-rank p<0.05).</p><p>§DCM onset was observed in less than 50% of patients, so no median value can be calculated.</p><p>Total n for <i>LTBP4</i> differs due to limited DNA availability in a few patients. For <i>SPP1</i>, patients included in the previous report about loss of ambulation (Pegoraro et al, 2011) were also excluded. <i>SPP1</i>: Secreted PhosphoProtein 1. <i>LTBP4</i>: latent transforming growth factor beta binding protein 4. DCM: dilated cardiomyopathy.</p><p>Median age at DCM onset by <i>SPP1</i> and <i>LTBP4</i> genotype.</p

Scatter plot of age at LoA and DCM onset in 57 patients shows no strong correlation (r = 0.31).

<p>Scatter plot of age at LoA and DCM onset in 57 patients shows no strong correlation (r = 0.31).</p

Kaplan-Meier plots of LoA by genotypes and steroid treatment.

<p>Triangles indicate censoring. (A) <i>SPP1</i> rs28357094 genotype: T/T red, T/G-G/G blue; (B) <i>LTBP4</i> rs10880: T/T red, C/C-C/T blue; (C) LTBP4 haplotype: IAAM/IAAM red, VTTT/VTTT grey, other blue; (D) rs28357094 genotype and steroid treatment: T/T red, T/G-G/G blue, solid treated (>1 year before LoA), dashed untreated; (E) rs10880 and steroid treatment: T/T red, C/C-C/T blue, solid treated, dashed untreated; (F) LTBP4 haplotype and steroid treatment: IAAM/IAAM red, other (including VTTT) grey, solid treated, dashed untreated.</p