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The autoimmune risk gene ZMIZ1 is a vitamin D responsive marker of a molecular phenotype of multiple sclerosis
N L Fewings1, P N Gatt1, F C McKay1
1Centre for Immunology and Allergy Research, Westmead Institute of Medical Research, University of Sydney, Sydney, New South Wales, Australia.
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.
Insights
The ZMIZ1 gene, linked to Multiple Sclerosis (MS) risk, is underexpressed in MS patients and its levels correlate with hundreds of other genes. This gene
Area of Science:
- Immunology
- Genetics
- Neuroscience
Background:
- Multiple Sclerosis (MS) involves peripheral immune cells, targeted by current therapies.
- The ZMIZ1 gene, associated with autoimmune diseases and MS risk, shows reduced expression in the blood of MS patients.
Purpose of the Study:
- To investigate the role and regulation of ZMIZ1 gene expression in Multiple Sclerosis.
- To explore ZMIZ1's correlation with other genes, heritability, cellular expression, and response to stimuli and therapies.
Main Methods:
- Analysis of three independent transcriptomic datasets.
- Assessment of ZMIZ1 gene expression stability, heritability, and cellular localization (plasmacytoid dendritic cells, non-classical monocytes).
- Evaluation of ZMIZ1 expression changes in response to calcipotriol, Epstein Barr Virus (EBV) EBNA-1 antibody titers, and MS therapies (fingolimod, dimethyl fumarate).
Main Results:
- ZMIZ1 expression is tightly correlated with hundreds of other genes.
- ZMIZ1 expression is partially heritable (0.26), stable over time, and primarily found in specific immune cells.
- ZMIZ1 levels are reduced in MS, increase with calcipotriol, associate with EBV EBNA-1 titers, and are altered by MS therapies.
Conclusions:
- Reduced ZMIZ1 expression is a phenotype associated with MS susceptibility.
- ZMIZ1 may serve as a novel clinical target for MS, potentially correlating with treatment response.
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