Abstract
The clinical course of multiple sclerosis (MS) is critically influenced by the interplay between inflammatory and neurodegenerative processes. The brain-derived neurotrophic factor (BDNF) Val66Met polymorphism (rs6265), one of the most studied single-nucleotide polymorphisms (SNPs), influences brain functioning and neurodegenerative processes in healthy individuals and in several neuropsychiatric diseases. However, the role of this polymorphism in MS is still controversial. In 218 relapsing–remitting (RR)-MS patients, we explored, at the time of diagnosis, the associations between the Val66Met polymorphism, clinical characteristics, and the cerebrospinal fluid (CSF) levels of a large set of pro-inflammatory and anti-inflammatory molecules. In addition, associations between Val66Met and structural MRI measures were assessed. We identified an association between the presence of Met and a combination of cytokines, identified by principal component analysis (PCA), including the pro-inflammatory molecules MCP-1, IL-8, TNF, Eotaxin, and MIP-1b. No significant associations emerged with clinical characteristics. Analysis of MRI measures evidenced reduced cortical thickness at the time of diagnosis in patients with Val66Met. We report for the first time an association between the Val66Met polymorphism and central inflammation in MS patients at the time of diagnosis. The role of this polymorphism in both inflammatory and neurodegenerative processes may explain its complex influence on the MS course.
Highlights
Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) that is nowadays representing one of the main causes of disability in young people [1].The clinical course of multiple sclerosis (MS) is highly variable and reflects the complex pathogenesis characterized by inflammation and neurodegeneration already detectable in the initial stages of the disease
brain-derived neurotrophic factor (BDNF) released in response to neuronal activity critically regulates glutamatergic transmission and synaptic plasticity [18,19]
BDNF is actively secreted by the immune cells of RR-MS patients during relapses and in the recovery phases [20]
Summary
Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) that is nowadays representing one of the main causes of disability in young people [1]. The brain-derived neurotrophic factor (BDNF) gene is located on chromosome 11p13, and the variant rs6265 (NM_001143810.1:c (196G > A) on ref genomes GRCh38/hg, Human Genome Variant Society, http://www.hgvs.org/mutnomen) represents one of the most widely studied single-nucleotide polymorphisms (SNPs) This SNP, known as “Val66Met”, produces a valine (Val) to methionine (Met) change at position 66 (p.Val66Met) of the proBDNF protein (NP_001137282.1). It is classified as a benign polymorphism according to ACMG guidelines [7], several reports consider rs6265 a possible risk factor, as related to the impairment in BDNF activity-dependent BDNF secretion [8]. To explore whether the BDNF Val66Met polymorphism could influence the inflammatory response in MS, we analyzed the associations between this SNP and the CSF levels of a large set of pro-inflammatory and anti-inflammatory molecules in a group of relapsing–remitting (RR)-MS patients at the time of diagnosis
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