Genetic Contribution to Medium-Term Disease Activity in Multiple Sclerosis.
Mol Neurobiol
; 2024 Jun 08.
Article
en En
| MEDLINE
| ID: mdl-38850349
ABSTRACT
Multiple sclerosis (MS) is a complex disorder characterized by high heterogeneity in terms of phenotypic expression, prognosis and treatment response. In the present study, we aimed to explore the genetic contribution to MS disease activity at different levels genes, pathways and tissue-specific networks. Two cohorts of relapsing-remitting MS patients who started a first-line treatment (n = 1294) were enrolled to evaluate the genetic association with disease activity after 4 years of follow-up. The analyses were performed at whole-genome SNP and gene level, followed by the construction of gene-gene interaction networks specific for brain and lymphocytes. The resulting gene modules were evaluated to highlight key players from a topological and functional perspective. We identified 23 variants and 223 genes with suggestive association to 4-years disease activity, highlighting genes like PON2 involved in oxidative stress and in mitochondria functions and other genes, like ILRUN, involved in the modulation of the immune system. Network analyses led to the identification of a brain module composed of 228 genes and a lymphocytes module composed of 287 genes. The network analysis allowed us to prioritize genes relevant for their topological properties; among them, there are MPHOSPH9 (connector hub in both brain and lymphocyte module) and OPA1 (in brain module), two genes already implicated in MS. Modules showed the enrichment of both shared and tissue-specific pathways, mainly implicated in inflammation. In conclusion, our results suggest that the processes underlying disease activity act on shared mechanisms across brain and lymphocyte tissues.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Idioma:
En
Revista:
Mol Neurobiol
Asunto de la revista:
BIOLOGIA MOLECULAR
/
NEUROLOGIA
Año:
2024
Tipo del documento:
Article
País de afiliación:
Italia
Pais de publicación:
Estados Unidos