The autoimmune risk gene ZMIZ1 is a vitamin D responsive marker of a molecular phenotype of multiple sclerosis

J Autoimmun. 2017 Mar;78:57-69. doi: 10.1016/j.jaut.2016.12.006. Epub 2017 Jan 4.

Abstract

Multiple Sclerosis (MS) is a neurological condition driven in part by immune cells from the peripheral circulation, the targets for current successful therapies. The autoimmune and MS risk gene ZMIZ1 is underexpressed in blood in people with MS. We show that, from three independent sets of transcriptomic data, expression of ZMIZ1 is tightly correlated with that of hundreds of other genes. Further we show expression is partially heritable (heritability 0.26), relatively stable over time, predominantly in plasmacytoid dendritic cells and non-classical monocytes, and that levels of ZMIZ1 protein expression are reduced in MS. ZMIZ1 gene expression is increased in response to calcipotriol (1,25 Vitamin D3) (p < 0.0003) and associated with Epstein Barr Virus (EBV) EBNA-1 antibody titre (p < 0.004). MS therapies fingolimod and dimethyl fumarate altered blood ZMIZ1 gene expression compared to untreated MS. The phenotype indicates susceptibility to MS, and may correspond with clinical response and represent a novel clinical target.

Keywords: Autoimmunity; Biomarker; Gene expression; Genetics; Multiple sclerosis; ZMIZ1.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Autoimmunity / genetics*
  • Biomarkers
  • Case-Control Studies
  • Dendritic Cells / immunology
  • Dendritic Cells / metabolism
  • Disease Susceptibility
  • Epstein-Barr Virus Infections / complications
  • Epstein-Barr Virus Infections / immunology
  • Female
  • Gene Expression Profiling
  • Gene Expression Regulation
  • Genotype
  • Herpesvirus 4, Human / immunology
  • Humans
  • Inheritance Patterns
  • Male
  • Middle Aged
  • Monocytes / immunology
  • Monocytes / metabolism
  • Multiple Sclerosis / etiology*
  • Multiple Sclerosis / metabolism*
  • Multiple Sclerosis / pathology
  • Phenotype*
  • Polymorphism, Single Nucleotide
  • Seasons
  • Transcription Factors / genetics*
  • Transcription Factors / metabolism
  • Vitamin D / metabolism*
  • Vitamin D / pharmacology
  • Young Adult

Substances

  • Biomarkers
  • Transcription Factors
  • ZMIZ1 protein, human
  • Vitamin D