title: The autoimmune risk gene ZMIZ1 is a vitamin D responsive marker of a molecular phenotype of multiple sclerosis.
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.
authors.affiliation: Centre for Immunology and Allergy Research, Westmead Institute of Medical Research, University of Sydney, Sydney, New South Wales, Australia.
authors.forename: N L
authors.initials: NL
authors.lastname: Fewings
authors.affiliation: Centre for Immunology and Allergy Research, Westmead Institute of Medical Research, University of Sydney, Sydney, New South Wales, Australia.
authors.forename: P N
authors.initials: PN
authors.lastname: Gatt
authors.affiliation: Centre for Immunology and Allergy Research, Westmead Institute of Medical Research, University of Sydney, Sydney, New South Wales, Australia.
authors.forename: F C
authors.initials: FC
authors.lastname: McKay
authors.affiliation: Centre for Immunology and Allergy Research, Westmead Institute of Medical Research, University of Sydney, Sydney, New South Wales, Australia.
authors.forename: G P
authors.initials: GP
authors.lastname: Parnell
authors.affiliation: Centre for Immunology and Allergy Research, Westmead Institute of Medical Research, University of Sydney, Sydney, New South Wales, Australia.
authors.forename: S D
authors.initials: SD
authors.lastname: Schibeci
authors.affiliation: Centre for Immunology and Allergy Research, Westmead Institute of Medical Research, University of Sydney, Sydney, New South Wales, Australia.
authors.forename: J
authors.initials: J
authors.lastname: Edwards
authors.affiliation: Centre for Immunology and Allergy Research, Westmead Institute of Medical Research, University of Sydney, Sydney, New South Wales, Australia.
authors.forename: M A
authors.initials: MA
authors.lastname: Basuki
authors.affiliation: University of Queensland, Diamantina Institute, Translational Research Institute, The Queensland Brain Institute, University of Queensland, Australia.
authors.forename: A
authors.initials: A
authors.lastname: Goldinger
authors.affiliation: 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.
authors.forename: M J
authors.initials: MJ
authors.lastname: Fabis-Pedrini
authors.affiliation: Institute for Immunology and Infectious Diseases, Murdoch University, Murdoch, Western Australia, Australia.
authors.forename: A G
authors.initials: AG
authors.lastname: Kermode
authors.affiliation: 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.
authors.forename: C P
authors.initials: CP
authors.lastname: Manrique
authors.affiliation: 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.
authors.forename: J L
authors.initials: JL
authors.lastname: McCauley
authors.affiliation: Department of Neurology, University of California San Francisco, USA.
authors.forename: D
authors.initials: D
authors.lastname: Nickles
authors.affiliation: Department of Neurology, University of California San Francisco, USA.
authors.forename: S E
authors.initials: SE
authors.lastname: Baranzini
authors.affiliation: Western Clinical School, University of Sydney, Westmead Hospital, Sydney, New South Wales, Australia.
authors.forename: T
authors.initials: T
authors.lastname: Burke
authors.affiliation: 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.
authors.forename: S
authors.initials: S
authors.lastname: Vucic
authors.affiliation: 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.
authors.forename: G J
authors.initials: GJ
authors.lastname: Stewart
authors.affiliation: Western Clinical School, University of Sydney, Westmead Hospital, Sydney, New South Wales, Australia. Electronic address: david.booth@sydney.edu.au.
authors.forename: D R
authors.initials: DR
authors.lastname: Booth
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015551:Autoimmunity / Q000235:genetics*; D015415:Biomarkers; D016022:Case-Control Studies; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D004198:Disease Susceptibility; D020031:Epstein-Barr Virus Infections / Q000150:complications / Q000276:immunology; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D005838:Genotype; D004854:Herpesvirus 4, Human / Q000276:immunology; D006801:Humans; D040582:Inheritance Patterns; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000276:immunology / Q000378:metabolism; D009103:Multiple Sclerosis / Q000209:etiology* / Q000378:metabolism* / Q000473:pathology; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D012621:Seasons; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D014807:Vitamin D / Q000378:metabolism* / Q000494:pharmacology; D055815:Young Adult
chemical_list: D015415:Biomarkers; D014157:Transcription Factors; C480599:ZMIZ1 protein, human; D014807:Vitamin D
keywords: Autoimmunity; Biomarker; Gene expression; Genetics; Multiple sclerosis; ZMIZ1