BDNF rs6265 polymorphism methylation in Multiple Sclerosis: A possible marker of disease progression

Abstract

IntroductionBrain-Derived Neurotrophic Factor (BDNF) and its most common polymorphism Val66Met are known to have a role in Multiple Sclerosis (MS) pathogenesis. Evidence is accumulating that there is an involvement of DNA methylation in the regulation of BDNF expression. The aim of this study was to assess in blood samples of MS patients the correlation between the methylation status of the CpG site near BDNF-Val66Met polymorphism and the severity of the disease.MethodsWe recruited 209 MS patients that were genotyped for the BDNF Val66Met polymorphism. For each patient we quantitatively measured the methylation level of cytosine included in the exonic CpG site that can be created or abolished by the Val66Met BDNF polymorphism. Furthermore, we analyzed the clinical history of each patient and determined the time elapsed since the onset of the disease and an EDSS score of 6.0.ResultsThe genetic analysis identified 122 (58.4%) subjects carrying the Val/Val genotype, 81 (38.8%) with Val/Met genotype, and 6 (2.8%) carrying the Met/Met genotype. When the endpoint of an EDSS score of 6 was taken into account by means of a survival analysis, 52 failures (i.e., reaching an EDSS score of 6) were reported. When the sample was stratified according to the percentage of the BDNF methylation, subjects falling below the median (median methylation = 81%) were at higher risk of failure (IRD = 0.016; 95%CI = 0.0050–0.0279; p = 0.004).ConclusionsIn patients with a high disease progression the hypomethylation of the BDNF gene could increase the secretion of the protective neurotrophin, so epigenetic modifications could be the organism response to limit a brain functional reserve loss. Our study suggests that the percentage of methylation of the BDNF gene could be used as a prognostic factor for disease progression toward a high disability in MS patient.

What is the role of Brain derived neurotrophic factor in Multiple Sclerosis neuroinflammation?

“…If BDNF methylation is considered as an epiphenomenon of the disease activity (or better of the neuroinflammation status), it might help to differentiate patients with a higher degree of inflammation from patients with a lower ones. If these data will be confirmed by other studies, BDNF rs6265 polymorphism methylation could become a valid prognostic factor in MS to precociously recognise patients with a more severe disease from those with a milder one [64] .…”

“…New advances in the epigenetic field, highlight the role of BDNF antisense RNA (BDNF-AS), a naturally conserved long noncoding RNA, and of DNA methylation, in the regulation of BDNF expression in MS and in several neurological diseases [60][61][62][63] . So far, only few studies have been published on this argument [64] .…”

“…Latest advances in the field of epigenetics highlight the role of epigenetic mechanisms, such as methylation, in controlling key biological processes. The presence of rs6265 SNP is not a prognostic factor for reaching a more severe Expanded Disability Status Scale (EDSS) [64] . When the percentage of methylation of the BDNF gene is considered, a lower percentage is associated with higher odds in achieving significant disability regardless of its polymorphism.…”

“…Patients with more severe inflammation could appeal to a de-methylation to have a higher secretion of BDNF, preserving better CNS functions. The same patients tend to reach a more severe disability score by depleting the functional reserves of the brain at a faster rate [64] . If BDNF methylation is considered as an epiphenomenon of the disease activity (or better of the neuroinflammation status), it might help to differentiate patients with a higher degree of inflammation from patients with a lower ones.…”

Aggressive multiple sclerosis (1): Towards a definition of the phenotype

“… 85 , 86 Genetically determined axonal response to inflammation and environmental factors might be associated with clinical outcome and disability progression in MS. An intriguing example was the detection that allelic variants of the neuroprotective ciliary neurotrophic factor (CNTF) were associated with disease onset, course and severity of experimental autoimmune encephalomyelitis (EAE) in mice. 87 Furthermore, polymorphisms of the brain-derived neurotrophic factor (BDNF) have in some studies been shown to impact on grey matter tissue damage in MS. 64 However, current data on gene variants associated with aggressive MS are very sparse and controversial; additional genetic studies may determine whether the clinical cohort of aggressive MS can be genetically distinguished from other disease phenotypes.…”