BDNF rs6265 polymorphism methylation in Multiple Sclerosis

A possible marker of disease progression

Viviana Nociti, Massimo Santoro, Davide Quaranta, Francesco Antonio Losavio, Chiara De Fino, Rocco Giordano, Nicole Palomba, Paolo Maria Rossini, Franca Rosa Guerini, Mario Clerici, Domenico Caputo, Massimiliano Mirabella

Research output: Contribution to journalArticle

Abstract

Introduction Brain-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. Methods We 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. Results The 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). Conclusions In 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.

Original languageEnglish
Article numbere0206140
JournalPLoS One
Volume13
Issue number10
DOIs
Publication statusPublished - Oct 1 2018

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neurotrophins
Methylation
Brain-Derived Neurotrophic Factor
sclerosis
Polymorphism
disease course
methylation
Multiple Sclerosis
Disease Progression
genetic polymorphism
brain
Genotype
Accidental Falls
Genes
genotype
Cognitive Reserve
Cytosine
Nerve Growth Factors
DNA Methylation
Survival Analysis

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

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Nociti, V., Santoro, M., Quaranta, D., Losavio, F. A., De Fino, C., Giordano, R., ... Mirabella, M. (2018). BDNF rs6265 polymorphism methylation in Multiple Sclerosis: A possible marker of disease progression. PLoS One, 13(10), [e0206140]. https://doi.org/10.1371/journal.pone.0206140

BDNF rs6265 polymorphism methylation in Multiple Sclerosis : A possible marker of disease progression. / Nociti, Viviana; Santoro, Massimo; Quaranta, Davide; Losavio, Francesco Antonio; De Fino, Chiara; Giordano, Rocco; Palomba, Nicole; Rossini, Paolo Maria; Guerini, Franca Rosa; Clerici, Mario; Caputo, Domenico; Mirabella, Massimiliano.

In: PLoS One, Vol. 13, No. 10, e0206140, 01.10.2018.

Research output: Contribution to journalArticle

Nociti, V, Santoro, M, Quaranta, D, Losavio, FA, De Fino, C, Giordano, R, Palomba, N, Rossini, PM, Guerini, FR, Clerici, M, Caputo, D & Mirabella, M 2018, 'BDNF rs6265 polymorphism methylation in Multiple Sclerosis: A possible marker of disease progression', PLoS One, vol. 13, no. 10, e0206140. https://doi.org/10.1371/journal.pone.0206140
Nociti, Viviana ; Santoro, Massimo ; Quaranta, Davide ; Losavio, Francesco Antonio ; De Fino, Chiara ; Giordano, Rocco ; Palomba, Nicole ; Rossini, Paolo Maria ; Guerini, Franca Rosa ; Clerici, Mario ; Caputo, Domenico ; Mirabella, Massimiliano. / BDNF rs6265 polymorphism methylation in Multiple Sclerosis : A possible marker of disease progression. In: PLoS One. 2018 ; Vol. 13, No. 10.
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abstract = "Introduction Brain-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. Methods We 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. Results The 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). Conclusions In 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.",
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AU - Nociti, Viviana

AU - Santoro, Massimo

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AU - Losavio, Francesco Antonio

AU - De Fino, Chiara

AU - Giordano, Rocco

AU - Palomba, Nicole

AU - Rossini, Paolo Maria

AU - Guerini, Franca Rosa

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AU - Caputo, Domenico

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N2 - Introduction Brain-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. Methods We 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. Results The 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). Conclusions In 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.

AB - Introduction Brain-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. Methods We 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. Results The 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). Conclusions In 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.

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