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LTBP4, SPP1, and CD40 Variants: Genetic Modifiers of Duchenne Muscular Dystrophy Analyzed in Serbian Patients
Ana Kosac1, Jovan Pesovic2, Lana Radenkovic2
1Department of Neurology, Clinic of Neurology and Psychiatry for Children and Youth, 11000 Belgrade, Serbia.
Background:
Clinical course variability in Duchenne muscular dystrophy (DMD) is partially explained by the mutation location in the DMD gene and variants in modifier genes. We assessed the effect of the SPP1, CD40, and LTBP4 genes and DMD mutation location on loss of ambulation (LoA).
Methods:
SNPs in SPP1-rs28357094, LTBP4-rs2303729, rs1131620, rs1051303, rs10880, and CD40-rs1883832 were genotyped, and their effect was assessed by survival and hierarchical cluster analysis.
Results:
Patients on glucocorticoid corticosteroid (GC) therapy experienced LoA one year later (p = 0.04). The modifying effect of SPP1 and CD40 variants, as well as LTBP4 haplotypes, was not observed using a log-rank test and multivariant Cox regression analysis. Cluster analysis revealed two subgroups with statistical trends in differences in age at LoA. Almost all patients in the cluster with later LoA had the protective IAAM LTBP4 haplotype and statistically significantly fewer CD40 genotypes with harmful T allele and "distal" DMD mutations.
Conclusions:
The modifying effect of SPP1, CD40, and LTBP4 was not replicated in Serbian patients, although our cohort was comparable in terms of its DMD mutation type distribution, SNP allele frequencies, and GC-positive effect with other European cohorts. Cluster analysis may be able to identify patient subgroups carrying a combination of the genetic variants that modify LoA.
Insights
Genetic variants in SPP1, CD40, and LTBP4 did not significantly modify Duchenne muscular dystrophy (DMD) progression in Serbian patients. However, cluster analysis suggested potential subgroup identification based on combined genetic factors influencing loss of ambulation (LoA).
Area of Science:
- Genetics and Genomics
- Neurology
- Biomedical Research
Background:
- Duchenne muscular dystrophy (DMD) exhibits variable clinical progression.
- Mutation location within the DMD gene and genetic modifiers influence disease course.
- Investigating SPP1, CD40, and LTBP4 gene variants as potential modifiers of DMD.
Purpose of the Study:
- To assess the impact of SPP1, CD40, and LTBP4 gene variants on the loss of ambulation (LoA) in Duchenne muscular dystrophy (DMD) patients.
- To evaluate the combined effect of these genetic variants and DMD mutation location on disease progression.
- To explore the utility of hierarchical cluster analysis in identifying patient subgroups with distinct LoA timelines.
Main Methods:
- Genotyping of single nucleotide polymorphisms (SNPs) in SPP1, LTBP4, and CD40 genes.
- Survival analysis using log-rank test and multivariant Cox regression.
- Hierarchical cluster analysis to identify patient subgroups based on age at LoA.
Main Results:
- Glucocorticoid (GC) therapy was associated with a delayed LoA by one year (p=0.04).
- No significant modifying effect of individual SPP1 variants, CD40 variants, or LTBP4 haplotypes on LoA was detected.
- Cluster analysis identified two subgroups with trends in LoA, where one subgroup with later LoA possessed protective LTBP4 haplotypes, fewer harmful CD40 genotypes, and distal DMD mutations.
Conclusions:
- The investigated genetic variants (SPP1, CD40, LTBP4) did not show a consistent modifying effect on LoA in Serbian DMD patients.
- Despite comparable cohort characteristics to other European studies, replication of modifier effects was not achieved.
- Hierarchical cluster analysis shows promise in identifying DMD patient subgroups based on combined genetic variants that may influence LoA.
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