DUCHENNE MUSCULAR DYSTROPHY - PHYSIOTHERAPY: P.302Genetic association study of articular range of motion in the CINRG Duchenne natural history study

Abstract

Joint contracture severity in DMD is variable between patients with comparable muscle weakness. We planned a genetic association study of contracture severity in participants in the CINRG Duchenne natural history study. We selected 109 participants of European American ancestry for genotyping with the illumina exome chip, in order to minimize population stratification bias. SNPs with minor allele frequency >0.05 were included in the analyses. Range of motion (ROM) was assessed using a standard goniometer. Prevalent DMD contractures were measured on the dominant side: elbow extension (n=104), wrist extension (n=104), knee extension (n=62), and ankle dorsiflexion (n=61). A linear model of association between articular ROM and genotype was used, with brooke upper extremity score and vignos lower extremity score as covariates, to adjust for muscle weakness in upper or lower limbs as relevant. QQ plots were visualized in order to control for type I or II error inflation. A bonferroni correction for 27,025 SNPs with MAF>0.05 was applied, leading to ``exome-wide'' significance of P=1.85*10-6. A more permissive ``suggestive'' threshold of P=10-4 was also considered. The only exome-wide significant association signal (P=1.36*10-7) was observed using an autosomal dominant inheritance model for rs12506517 (70kb upstream BANK1, encoding a B-cell-specific scaffold protein that mobilizes Ca++ from intracellular stores). This protein promotes Lyn-mediated tyrosine phosphorylation of inositol 1,4,5-trisphosphate (IP3) receptors. Several ``suggestive'' signals were observed, including SNPs in FAM26F (Ca++ homeostasis regulator), DST, DYSF, and LTBP4. This study suggests a role of SNPs in Ca++ homeostasis genes and other genes in predisposing DMD patients to early contractures. Further studies are needed to validate these associations and elucidate their mechanistic underpinnings, before these genes and the corresponding proteins can be considered as biomarkers or therapeutic targets.