engleski

The burden of rare genetic variants in genes involved in tumor necrosis factor (TNF) signalling pathway in multiple sclerosis (MS).

Introduction: MS is a chronic inflammatory disease of central nervous system with widely studied, however still poorly understood genetic contribution. Several lines of evidence imply an important role of TNF pathway in the pathogenesis of MS including inflammatory demyelination of central nervous system observed in TNF receptor-associated periodic syndrome (TRAPS) caused by rare mutations in TNFRSF1A. Therefore, we hypothesized that an increased mutation burden in genes involved in TNF signalling pathway may trigger inflammation in MS.Materials and Methods: Nextera Coding Exome enrichment was used to perform Whole exome sequencing of 35 patients with familial MS, 43 patients with sporadic MS and 91 population matched controls. Genotypes were called using GATK toolkit. The selection of variants among 110 genes involved in TNF signalling pathway (KEGG database) was narrowed down by evaluation of functional impact of in silico predictors: Meta-SVM (when described as damaging) and/or CADD (when N > 20). Results: We identified 56 rare potentially pathogenic genetic variants in 37 genes. We detected a statistically significant increased burden of rare genetic variants in sporadic (x2=5.42, p=0.02), but not in the familial cases of MS (x2=0.13, p=0.72), when compared to controls. Conclusions: We found evidence for an increased burden of rare genetic variants in genes of the TNF signalling pathway in sporadic MS patients, which further supports its pathogenetic role in MS.

Multiple Sclerosis, TNF pathway, Burden

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