Maltby Vicki E, Lea Rodney A, Sanders Katherine A, White Nicole, Benton Miles C, Scott Rodney J, Lechner-Scott Jeannette
Centre for Information Based Medicine, Hunter Medical Research Institute, Locked Bag 1, Hunter Region Mail Centre, Newcastle, 2310 Australia.
School of Biomedical Sciences and Pharmacy, University of Newcastle, Newcastle, Australia.
Clin Epigenetics. 2017 Jul 18;9:71. doi: 10.1186/s13148-017-0371-1. eCollection 2017.
Although many genetic variants have been associated with multiple sclerosis (MS) risk, they do not explain all the disease risk and there remains uncertainty as to how these variants contribute to disease. DNA methylation is an epigenetic mechanism that can influence gene expression and has the potential to mediate the effects of environmental factors on MS. In a previous study, we found a differentially methylation region (DMR) at MHC that was associated within relapsing-remitting MS (RRMS) patients in CD4 T cells. This study aimed to confirm this earlier finding in an independent RRMS cohort of treatment-naïve female patients.
Total genomic DNA was extracted from CD4 T cells of 28 female RRMS and 22 age-matched healthy controls subjects. DNA was bisulfite-converted and hybridised to Illumina 450K arrays. Beta values for all CpGs were analysed using the DMPFinder function in the MINFI program, and a follow-up prioritisation process was applied to identify the most robust MS-associated DMRs.
This study confirmed our previous findings of a hypomethylated DMR at and a hypermethylated DMR at in this RRMS patient cohort. In addition, we identified a large independent DMR at MHC, whereby 11 CpGs in were hypermethylated in MS cases compared to controls (max. ∆beta = 0.19, = 2.1 × 10). We did not find evidence that SNP genotype was influencing the DMR in this cohort. A smaller DMR was also identified at , and two non-MHC DMRs at on chr1 and on chr8 were also identified.
The findings from this study confirm our previous results of a DMR at and also suggest hypermethylation in an independent MHC locus, , is associated with MS Taken together, our results highlight the importance of epigenetic factors at the MHC locus in MS independent of treatment, age and sex. Prospective studies are now required to discern whether methylation at MHC is involved in influencing risk of disease onset or whether the disease itself has altered the methylation profile.
尽管许多基因变异与多发性硬化症（MS）风险相关，但它们并不能解释所有的疾病风险，而且这些变异如何导致疾病仍存在不确定性。DNA甲基化是一种表观遗传机制，可影响基因表达，并有可能介导环境因素对MS的影响。在之前的一项研究中，我们在MHC区域发现了一个差异甲基化区域（DMR），该区域与复发缓解型MS（RRMS）患者CD4 T细胞中的DMR相关。本研究旨在在一个未经治疗的女性RRMS独立队列中证实这一早期发现。
从28名女性RRMS患者和22名年龄匹配的健康对照者的CD4 T细胞中提取总基因组DNA。DNA经亚硫酸氢盐转化后与Illumina 450K芯片杂交。使用MINFI程序中的DMPFinder功能分析所有CpG的β值，并应用后续的优先级排序过程来识别最可靠的与MS相关的DMR。
本研究证实了我们之前在该RRMS患者队列中发现的位于[具体位置1]的低甲基化DMR和位于[具体位置2]的高甲基化DMR。此外，我们在MHC区域发现了一个大的独立DMR，与对照组相比，MS病例中[具体区域]的11个CpG呈高甲基化（最大∆β = 0.19，P = 2.1×10）。我们没有发现SNP基因型影响该队列中DMR的证据。在[具体位置3]也发现了一个较小的DMR，在chr1上的[具体位置4]和chr8上的[具体位置5]还发现了两个非MHC DMR。
本研究结果证实了我们之前在[具体位置]发现DMR的结果，也表明在一个独立的MHC位点[具体位置]的高甲基化与MS相关。综上所述，我们的结果强调了MHC位点表观遗传因素在MS中的重要性，且独立于治疗、年龄和性别。现在需要进行前瞻性研究，以确定MHC区域的甲基化是否参与影响疾病发病风险，或者疾病本身是否改变了甲基化谱。
