Importance of SPP1 genotype as a covariate in clinical trials in Duchenne muscular dystrophy

Abstract

Objective: To test the effect of the single nucleotide polymorphism -66 T>G (rs28357094) in the osteopontin gene (SPP1) on functional measures over 12 months in Duchenne muscular dystrophy (DMD).

Methods: This study was conducted on a cohort of ambulatory patients with DMD from a network of Italian neuromuscular centers, evaluated longitudinally with the north star ambulatory assessment (NSAA) and the 6-minute walk test (6MWT) at study entry and after 12 months. Genotype at rs28357094 was determined after completion of the clinical evaluations. Patients were stratified in 2 groups according to a dominant model (TT homozygotes vs TG heterozygotes and GG homozygotes) and clinical data were retrospectively compared between groups.

Results: Eighty patients were selected (age 4.1-19.3 years; mean 8.3 ± 2.7 SD). There were no differences in age or steroid treatment between the 2 subgroups. Paired t test showed a significant difference in both NSAA (p = 0.013) and 6MWT (p = 0.03) between baseline and follow-up after 12 months in patients with DMD carrying the G allele. The difference was not significant in the T subgroup. The analysis of covariance using age and baseline values as covariate and SPP1 genotype as fixed effect showed that these parameters are significantly correlated with the 12-month values.

Conclusions: These data provide evidence of the role of SPP1 genotype as a disease modifier in DMD and support its relevance in the selection of homogeneous groups of patients for future clinical trials.

Figure. Patients with Duchenne muscular dystrophy carrying the G allele at rs28357094 deteriorated faster than patients carrying the T allele

The mean values for North Star Ambulatory Assessment (NSAA) (A) and 6-Minute Walk Test (6MWT) (B) at T0 and T12 in the T and G subgroups are shown. T0–T12 mean differences in NSAA and 6MWT are significant only in the G subgroup of patients. Vertical bars represent 95% confidence intervals. A scatterplot of T0–T12 changes in NSAA (C) and 6MWT (D) in the T and G subgroups are shown. The superimposed linear regression shows a steeper decline in the G subgroup (NSAA slope estimates: T −0.17, G −1.12, SE: 0.13, p < 0.001; 6MWT slope estimates: T −5.76, G −14.44, SE 2.02, p < 0.001).