Genetic Modifiers of Duchenne Muscular Dystrophy in Chinese Patients

Abstract

Background: Duchenne muscular dystrophy (DMD) is a fatal, X-linked recessive muscle disorder characterized by heterogeneous progression and severity. We aimed to study the effects of single nucleotide polymorphisms (SNPs) in SPP1 and LTBP4 on DMD progression in Chinese patients. Methods: We genotyped LTBP4 haplotypes and the SPP1 promoter SNPs rs28357094, rs11730582, and rs17524488 in 326 patients registered in the neuromuscular database of The First Affiliated Hospital of Sun Yat-sen University. Kaplan-Meier curves and log-rank tests were used to estimate and compare median age at loss of ambulation, while Cox proportional hazard regression models were used as to analyze the effects of glucocorticoids treatments, DMD genotype, and SPP1 / LTBP4 SNPs on loss of ambulation. Results: The CC/CT genotype at rs11730582 was associated with a 1.33-year delay in ambulation loss ( p = 0.006), with hazard ratio 0.63 ( p = 0.008), in patients with truncated DMD genotype and undergoing steroid treatment. On the other hand, rs17524488 in SPP1 and the IAAM/IAAM haplotype in LTBP4 were not associated with time to ambulation loss. Conclusions: SPP1 rs11730582 is a genetic modifier of the long-term effects of steroid treatment in Chinese DMD patients. Thus, any future clinical study in DMD should adjust for glucocorticoids use, DMD genotype, and SPP1 polymorphisms.

Genetic Modifiers and Phenotype of Duchenne Muscular Dystrophy: A Systematic Review and Meta-Analysis

“…Of the 259 studies identified, 8 met the inclusion criteria and were included in the systematic review [ 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 ], and 4 were included in the meta-analysis ( Table 1 and Figure 1 ) [ 20 , 21 , 22 , 24 ]. Four studies were excluded for various reasons ( Supplementary Table S1 ) [ 34 , 35 , 36 , 37 ].…”

“…Finally, regarding SPP1 rs11730582 and rs17524488, only rs11730582 genotype C showed a protective association, with an HR = 0.63 (95% CI: 0.45, 0.89) [21]. no significant effect [20,21]. SPP1 rs28357094 showed no association [20,24].…”

“…For SPP1 rs28357094, one of the two studies showed an association [20], while rs28357094 showed no association in the nonglucocorticoid subgroup [21]. Finally, SPP1 rs11730582 also showed an association, with the C genotype being protective (dominant model) [21]. Interactions between LTBP4 and THBS1 (∆means) LTBP4 rs710160 TT + THBS1 rs2725797 TT: ∆LoA = 0y.…”

“…In 2017, a systematic review suggested the association of some of these genetic variants with LoA [ 18 ]. Since then, new studies have been published that may improve the available evidence [ 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 ]. Therefore, this systematic review and meta-analysis aims to estimate the association of SPP1 rs28357094, LTBP4 haplotype IAAM, and other genes directly involved in the TGFβ pathway with the age at LoA and cardiac function in patients with DMD.…”

Matrilineal analysis of mutations in the DMD gene in a multigenerational South Indian cohort using DMD gene panel sequencing

“…Furthermore, the design of this panel allows us to add on additional probes covering other modifier genes like LTBP4, which is believed to accelerate muscle regeneration and alleviate muscle fibrosis by reducing TGF-β signalling. Phosphatidylinositol transfer protein α (PITPNA) and Jagged1 that ameliorate the pathology of DMD, Anxa6 that encodes annexin A6, a calcium-binding protein that regulates the injury pathway, and sarcolemmal resealing, decreased expression of TCTEX1D1 could be deleterious for the cardiac phenotype in patients with DMD and Osteopontin; encoded by the SPP1 gene which plays a role in DMD pathology modulating muscle inflammation and regeneration (Chen et al, 2020;Spitali et al, 2020;Vieira et al, 2015). We tested this panel on a set of 24 confirmed DMD patients from 22 families and the members from their matrilineage for up to four generations.…”