title: Interleukin-2 receptor-α proximal promoter hypomethylation is associated with multiple sclerosis.
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.
authors.affiliation: Multiple Sclerosis Division, The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Melbourne, VIC, Australia.
authors.forename: J
authors.initials: J
authors.lastname: Field
authors.affiliation: Multiple Sclerosis Division, The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Melbourne, VIC, Australia.
authors.forename: A
authors.initials: A
authors.lastname: Fox
authors.affiliation: Comparative Genomics Centre, James Cook University, Townsville, QLD, Australia.
authors.forename: M A
authors.initials: MA
authors.lastname: Jordan
authors.affiliation: Comparative Genomics Centre, James Cook University, Townsville, QLD, Australia.
authors.forename: A G
authors.initials: AG
authors.lastname: Baxter
authors.affiliation: Department of Medicine, University of Melbourne, Parkville, VIC, Australia.
authors.forename: T
authors.initials: T
authors.lastname: Spelman
authors.affiliation: Department of Medicine, University of Melbourne, Parkville, VIC, Australia.
authors.forename: M
authors.initials: M
authors.lastname: Gresle
authors.affiliation: Department of Medicine, University of Melbourne, Parkville, VIC, Australia.
authors.forename: H
authors.initials: H
authors.lastname: Butzkueven
authors.affiliation: The Melbourne Neuroscience Institute, University of Melbourne, Melbourne, VIC, Australia.
authors.forename: T J
authors.initials: TJ
authors.lastname: Kilpatrick
authors.affiliation: Multiple Sclerosis Division, The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Melbourne, VIC, Australia.|Department of Pathology, University of Melbourne, Parkville, VIC, Australia.
authors.forename: J P
authors.initials: JP
authors.lastname: Rubio
mesh_terms: D018899:CpG Islands; D019175:DNA Methylation; D015870:Gene Expression; D006801:Humans; D053645:Interleukin-2 Receptor alpha Subunit / Q000235:genetics*; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D013058:Mass Spectrometry; D009103:Multiple Sclerosis / Q000235:genetics*; D011401:Promoter Regions, Genetic; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D013601:T-Lymphocytes / Q000378:metabolism*
chemical_list: D053645:Interleukin-2 Receptor alpha Subunit