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Interleukin-2 receptor-α proximal promoter hypomethylation is associated with multiple sclerosis

Genes & Immunity volume 18, pages 59–66 (2017)Cite this article

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Abstract

Genetic studies have demonstrated association between single-nucleotide polymorphisms within the IL2RA (interleukin-2 receptor α-subunit) gene and risk of developing multiple sclerosis (MS); however, these variants do not have obvious functional consequences. DNA methylation is a source of genetic variation that could impact on autoimmune disease risk. We investigated DNA methylation of the IL2RA promoter in genomic DNA obtained from peripheral blood mononuclear cells and neural tissue using matrix-assisted laser desorption/ionization-time of flight (MALDI-TOF) mass spectrometry. A differential methylation profile of IL2RA was identified, suggesting that IL2RA expression was regulated by DNA methylation. We extended our analysis of DNA methylation to peripheral blood mononuclear cell (PBMC) of MS cases and controls using MALDI-TOF and Illumina HumanMethylation450 arrays. Analyses of CpG sites within the proximal promoter of IL2RA in PBMC showed no differences between MS cases and controls despite an increase in IL2RA expression. In contrast, we inferred significant DNA methylation differences specific to particular leukocyte subtypes in MS cases compared with controls by deconvolution of the array data. The decrease in methylation in patients correlated with an increase in IL2RA expression in T cells from MS cases in comparison with controls. Our data suggest that differential methylation of the IL2RA promoter in T cells could be an important pathogenic mechanism in MS.

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Acknowledgements

We thank all the people with MS and control persons who participated in this study, and are grateful to Jennifer Eckholdt and John Carey for their assistance with the collection of blood samples for this study. This work was supported by NHMRC Project Grants (nos 257518 and 509184) and JF was supported by a Multiple Sclerosis Research Australia Fellowship. This work was also funded by Multiple Sclerosis Research Australia, National Health and Medical Research Council Australia, Lions International and Rebecca L Cooper Foundation. MAJ is supported by an NHMRC/MSRA Betty Cuthbert fellowship. AGB is supported by an Australian National Health and Medical Research Council (NHMRC) Research Fellowship.

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Authors and Affiliations

  1. Multiple Sclerosis Division, The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Melbourne, VIC, Australia

    J Field, A Fox & J P Rubio

  2. Comparative Genomics Centre, James Cook University, Townsville, QLD, Australia

    M A Jordan & A G Baxter

  3. Department of Medicine, University of Melbourne, Parkville, VIC, Australia

    T Spelman, M Gresle & H Butzkueven

  4. The Melbourne Neuroscience Institute, University of Melbourne, Melbourne, VIC, Australia

    T J Kilpatrick

  5. Department of Pathology, University of Melbourne, Parkville, VIC, Australia

    J P Rubio

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  1. J Field
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Correspondence to J Field.

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Field, J., Fox, A., Jordan, M. et al. Interleukin-2 receptor-α proximal promoter hypomethylation is associated with multiple sclerosis. Genes Immun 18, 59–66 (2017). https://doi.org/10.1038/gene.2016.50

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