维生素D受体启动子DNA异常甲基化水平与视神经脊髓炎谱系疾病的关系
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摘要
目的探讨维生素D受体(vitamin D receptor,VDR)启动子DNA甲基化水平与神经脊髓炎谱系疾病(neuromyelitis optica spectrum disorders,NMOSD)及其残疾程度的相关性。方法收集NMOSD患者39例及健康对照16例,并根据EDSS评分将NMOSD组分为轻度组(EDSS≤2.5)及中重度组(EDSS>2.5)。检测外周血单个核细胞(peripheral blood mononuclear cell,PBMC)中VDR启动子DNA甲基化水平,并分析VDR启动子DNA甲基化水平与NMOSD及其残疾程度的相关性。结果①多因素logistics回归分析提示:CPG-3位点异常甲基化水平与NMOSD相关(OR=0.272,95%CI:0.112～0.662,P=0.004),CPG-14位点异常甲基化水平与NMOSD残疾程度相关(OR=4.013,95%CI:1.01～15.92,P=0.048)。②与健康对照组相比,NMOSD患者VDR mRNA上调了1.9倍,差异具有统计学意义(P=0.001)。结论 VDR启动子DNA异常甲基化水平可能与NMOSD及其残疾程度有关。
Objective To investigate the Methylation Status of vitamin D receptor(VDR) promoter in neuromyelitis optica spectrum disorders patients(NMOSD)and to analyze its relationship with NMOSD and the extended disability status scale(EDSS) score of NMOSD patients. Methods We assessed the VDR gene methylation/demethylation in peripheral blood mononuclear cells(PBMCs) from 39 NMOSD and 16 age-, gender-matched healthy controls. The DNA methylation levels of the VDR promoters were compared between the two groups. In addition, according to the EDSS score, the NMOSD components were mild(EDSS ≤2.5) and moderately severe(EDSS >2.5), Comparisons were made on the DNA methylation levels of the two groups of VDR promoters. Regression analysis was used to examine the correlation between DNA Methylation Level of VDR Promoter and NMOSD and Its Degree of Disability. Results ①Multivariate logistic regression analysis indicated that the abnormal methylation level of CPG-3 site was correlated with NMOSD(OR=0.272, 95% CI: 0.112～0.662, P=0.004), abnormal methylation level of CPG-14 site and NMOSD Degree of disability(OR=4.013, 95% CI: 1.01～15.92, P=0.048). ②A 1.9-fold increase in VDR mRNA levels was found in NMOSD patients compared to controls(P =0.001). Conclusion Abnormal methylation levels of VDR promoter DNA may be related to NMOSD and its degree of disability.
Objective To investigate the Methylation Status of vitamin D receptor(VDR) promoter in neuromyelitis optica spectrum disorders patients(NMOSD)and to analyze its relationship with NMOSD and the extended disability status scale(EDSS) score of NMOSD patients. Methods We assessed the VDR gene methylation/demethylation in peripheral blood mononuclear cells(PBMCs) from 39 NMOSD and 16 age-, gender-matched healthy controls. The DNA methylation levels of the VDR promoters were compared between the two groups. In addition, according to the EDSS score, the NMOSD components were mild(EDSS ≤2.5) and moderately severe(EDSS >2.5), Comparisons were made on the DNA methylation levels of the two groups of VDR promoters. Regression analysis was used to examine the correlation between DNA Methylation Level of VDR Promoter and NMOSD and Its Degree of Disability. Results ①Multivariate logistic regression analysis indicated that the abnormal methylation level of CPG-3 site was correlated with NMOSD(OR=0.272, 95% CI: 0.112～0.662, P=0.004), abnormal methylation level of CPG-14 site and NMOSD Degree of disability(OR=4.013, 95% CI: 1.01～15.92, P=0.048). ②A 1.9-fold increase in VDR mRNA levels was found in NMOSD patients compared to controls(P =0.001). Conclusion Abnormal methylation levels of VDR promoter DNA may be related to NMOSD and its degree of disability.
引文
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[2]KULAR L,LIU Y,RUHRMANN S,et al.DNA methylation as a mediator of HLA-DRB1*15:01 and a protective variant in multiple sclerosis[J].Nature Communications,2018,9(1):2397.
[3]MALTBY V E,GRAVES M C,LEA R A,et al.Genome-wide DNA methylation profiling of CD8+T cells shows a distinct epigenetic signature to CD4+T cells in multiple sclerosis patients[J].Clinl Epigenetics,2015,7(1):1-6
[4]PEREIRA F,BARBACHANO A,SINGH P K,et al.Vitamin Dhas wide regulatory effects on histone demethylase genes[J].Cell Cycle,2012,11(6):1081-1089.
[5]MORA JR,IWATA M,VON ANDRIAN UH.Vitamin effects on the immune system:vitamins A and D take centre stage[J].Nat Rev Immunol,2008,8(9):685-698.
[6]HART PH,GORMAN S,FINLAY-JONES JJ.Modulation of the immune system by UV radiation:more than just the effects of vitamin D?[J].Nat Rev Immunol,2011,11(9):584-596.
[7]CHUN RF,LIU PT,MODLIN RL,et al.Impact of vitamin D on immune function:lessons learned from genome-wide analysis[J].Front Physiol,2014,5(4):151.
[8]WEI R,CHRISTAKOS S.Mechanisms Underlying the Regulation of Innate and Adaptive Immunity by Vitamin D[J].Nutrients,2015,7(10):8251-8260.
[9]YAMSHCHIKOV AV,DESAI NS,BLUMBERG HM,et al.Vitamin D for treatment and prevention of infectious diseases:a systematic review of randomized controlled trials[J].Endocr Pract,2009,15(5):438-449.
[10]WINGERCHUK DM,BANWEL B,BENNET JL,et al.International panel for NMO diagnosis.International consensus diagnostic criteria for neuromyelitis optica spectrum disorders[J].Neurology,2015,85(2):177-189.
[11]MOORE JR,HUBLERD SL,NELSON CD,et al.1,25-Dihydroxyvitamin D3 increases the methionine cycle,CD4+T cell DNA methylation and Helios+Foxp3+T regulatory cells to reverse autoimmune neurodegenerative disease[J].Journal of Neuroimmunology,2018,324(15):100-114.
[12]O’BRIEN KM,SANDLER DP,XU Z,et al.Vitamin D,DNAmethylation,and breast cancer[J].Breast Cancer Research,2018,20(1):70.
[13]ZHU H,MI W,HUI L,et al.Whole-genome transcription and DNA methylation analysis of peripheral blood mononuclear cells identified aberrant gene regulation pathways in systemic lupus erythematosus[J].Arthritis Research&Therapy,2016,18(1):162.
[14]KULAR L,LIU Y,RUHRMANN S,et al.DNA methylation as a mediator of HLA-DRB1*15:01and a protective variant in multiple sclerosis[J].Nature Communications,2018,9(1):2397.
[15]赵俊杰.多发性硬化和视神经脊髓炎中DNA甲基化差异性的初步研究[D].大连:大连医科大学,2016.
[16]HUYNH JL,GARG P,THIN TH,et al.Epigenome-wide differences in pathology-free regions of multiple sclerosis-affected brains[J].Nature Neuroscience,2014,17(1):121-130.
[17]CHOMYK AM,VOLSKO C,TRIPATHI A,et al.DNA methylation in demyelinated multiple sclerosis hippocampus[J].Scientific Reports,2017,7(1):8696.
[18]NAIR N,WILSON AG,BARTON A.DNA methylation as a marker of response in rheumatoid arthritis[J].Pharmacogenomics,2017,18(4):1323-1332.
[19]ZHU H,BHAGATWALA J,HUANG Y,et al.Race/ethnicityspecific association of Vitamin D and global DNA methylation:cross-sectional and interventional findings[J].PLoS One,2016,11(4):e0152849.
[20]MARIK R,FACKLER M J,GABRIELSON E,et al.DNA methylation-related vitamin D receptor insensitivity in breast cancer[J].Cancer Biology&Therapy,2010,10(1):44-53.