Transcriptomic profile reveals gender-specific molecular mechanisms driving multiple sclerosis progression

PLoS One. 2014 Feb 28;9(2):e90482. doi: 10.1371/journal.pone.0090482. eCollection 2014.

Abstract

Background: Although the most common clinical presentation of multiple sclerosis (MS) is the so called Relapsing-Remitting MS (RRMS), the molecular mechanisms responsible for its progression are currently unknown. To tackle this problem, a whole-genome gene expression analysis has been performed on RRMS patients.

Results: The comparative analysis of the Affymetrix Human Gene 1.0 ST microarray data from peripheral blood leucocytes obtained from 25 patients in remission and relapse and 25 healthy subjects has revealed 174 genes altered in both remission and relapse, a high proportion of them showing what we have called "mirror pattern": they are upregulated in remission and downregulated in relapse or vice versa. The coexpression analysis of these genes has shown that they are organized in three female-specific and one male-specific modules.

Conclusions: The interpretation of the modules of the coexpression network suggests that Epstein-Barr virus (EBV) reactivation of B cells happens in MS relapses; however, qPCR expression data of the viral genes supports that hypothesis only in female patients, reinforcing the notion that different molecular processes drive disease progression in females and males. Besides, we propose that the "primed" state showed by neutrophils in women is an endogenous control mechanism triggered to keep EBV reactivation under control through vitamin B12 physiology. Finally, our results also point towards an important sex-specific role of non-coding RNA in MS.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • B-Lymphocytes / metabolism
  • B-Lymphocytes / virology
  • Disease Progression
  • Epstein-Barr Virus Infections / blood
  • Epstein-Barr Virus Infections / genetics
  • Epstein-Barr Virus Infections / virology
  • Female
  • Gene Regulatory Networks*
  • Herpesvirus 4, Human / genetics
  • Herpesvirus 4, Human / physiology
  • Humans
  • Leukocytes / metabolism
  • Leukocytes / virology
  • Male
  • Middle Aged
  • Models, Genetic
  • Multiple Sclerosis, Relapsing-Remitting / genetics*
  • Multiple Sclerosis, Relapsing-Remitting / pathology
  • Oligonucleotide Array Sequence Analysis / methods*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Sex Factors
  • Transcobalamins / genetics
  • Transcobalamins / metabolism
  • Transcriptome / genetics*
  • Virus Activation / genetics
  • Young Adult

Substances

  • Transcobalamins

Associated data

  • GEO/GSE41890

Grants and funding

This project has been supported by the Spanish Health Ministry (FIS project (PS09/02105) and the SAIOTEK program (SAIO11-PC11BN003 project) of the Basque Government. MMC and HI are supported by predoctoral grants from the Department of Education, University, and Research of the Basque Government. TCT is supported by a Río Hortega Grant from the Spanish Health Ministry. GZL is supported by the German Federal Ministry of Education and Research (Bernstein Center II, grant no. 01GQ1001A) and by the European Union Seventh Framework Programme FP7/2007-2013 under grant agreement n° PIEF-GA-2012-331800. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.