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

N L Fewings; P N Gatt; F C McKay; G P Parnell; S D Schibeci; J Edwards; M A Basuki; A Goldinger; M J Fabis-Pedrini; A G Kermode; C P Manrique; J L McCauley; D Nickles; S E Baranzini; T Burke; S Vucic; G J Stewart; D R Booth

doi:10.1016/j.jaut.2016.12.006

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.

Authors

N L Fewings¹, P N Gatt¹, F C McKay¹, G P Parnell¹, S D Schibeci¹, J Edwards¹, M A Basuki¹, A Goldinger², M J Fabis-Pedrini³, A G Kermode⁴, C P Manrique⁵, J L McCauley⁵, D Nickles⁶, S E Baranzini⁶, T Burke⁷, S Vucic⁸, G J Stewart⁸, D R Booth⁹

Affiliations

¹ Centre for Immunology and Allergy Research, Westmead Institute of Medical Research, University of Sydney, Sydney, New South Wales, Australia.
² University of Queensland, Diamantina Institute, Translational Research Institute, The Queensland Brain Institute, University of Queensland, Australia.
³ Western Australian Neuroscience Research Institute, University of Western Australia, Nedlands, Western Australia, Australia; Institute for Immunology and Infectious Diseases, Murdoch University, Murdoch, Western Australia, Australia.
⁴ Institute for Immunology and Infectious Diseases, Murdoch University, Murdoch, Western Australia, Australia.
⁵ John P. Hussman Institute for Human Genomics and the Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami, Miller School of Medicine, Miami, FL 33136, USA.
⁶ Department of Neurology, University of California San Francisco, USA.
⁷ Western Clinical School, University of Sydney, Westmead Hospital, Sydney, New South Wales, Australia.
⁸ Centre for Immunology and Allergy Research, Westmead Institute of Medical Research, University of Sydney, Sydney, New South Wales, Australia; Western Clinical School, University of Sydney, Westmead Hospital, Sydney, New South Wales, Australia.
⁹ Western Clinical School, University of Sydney, Westmead Hospital, Sydney, New South Wales, Australia. Electronic address: david.booth@sydney.edu.au.

PMID: 28063629
DOI: 10.1016/j.jaut.2016.12.006

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

Grants and funding

R01 NS088155/NS/NINDS NIH HHS/United States