Field J, Fox A, Jordan M A, Baxter A G, Spelman T, Gresle M, Butzkueven H, Kilpatrick T J, Rubio J P
Multiple Sclerosis Division, The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Melbourne, VIC, Australia.
Comparative Genomics Centre, James Cook University, Townsville, QLD, Australia.
Genes Immun. 2017 Mar;18(2):59-66. doi: 10.1038/gene.2016.50. Epub 2017 Jan 12.
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.
基因研究已证明白细胞介素2受体α亚基（IL2RA）基因内的单核苷酸多态性与多发性硬化症（MS）发病风险之间存在关联；然而，这些变异并没有明显的功能后果。DNA甲基化是一种可能影响自身免疫性疾病风险的遗传变异来源。我们使用基质辅助激光解吸/电离飞行时间（MALDI-TOF）质谱法研究了从外周血单核细胞和神经组织获得的基因组DNA中IL2RA启动子的DNA甲基化情况。确定了IL2RA的差异甲基化谱，表明IL2RA的表达受DNA甲基化调控。我们使用MALDI-TOF和Illumina HumanMethylation450芯片将DNA甲基化分析扩展到MS病例和对照的外周血单核细胞（PBMC）。尽管IL2RA表达增加，但PBMC中IL2RA近端启动子内的CpG位点分析显示MS病例和对照之间没有差异。相反，通过对芯片数据进行反卷积分析，我们推断MS病例与对照相比，特定白细胞亚群存在显著的DNA甲基化差异。与对照相比，患者甲基化的降低与MS病例T细胞中IL2RA表达的增加相关。我们的数据表明，T细胞中IL2RA启动子的差异甲基化可能是MS的一种重要致病机制。
