血清阳性与早期类风湿关节炎患者对甲氨蝶呤治疗反应的 LINE-1 甲基化之间的相关性。
Seropositivity-Dependent Association between LINE-1 Methylation and Response to Methotrexate Therapy in Early Rheumatoid Arthritis Patients.
机构信息
Medical Genetics Laboratory, Department of Neuroscience and Rehabilitation, University of Ferrara, 44121 Ferrara, Italy.
Laboratory of Immunorheumatology and Tissue Regeneration, IRCCS Istituto Ortopedico Rizzoli, 40136 Bologna, Italy.
出版信息
Genes (Basel). 2022 Nov 2;13(11):2012. doi: 10.3390/genes13112012.
BACKGROUND
Methotrexate (MTX) is considered the first choice among disease-modifying anti-rheumatic drugs (DMARDs) for rheumatoid arthritis (RA) treatment. However, response to it varies as approximately 40% of the patients do not respond and would lose the most effective period of treatment time. Therefore, having a predictive biomarker before starting MTX treatment is of utmost importance. Methylation of long interspersed nucleotide element-1 (LINE-1) is generally considered a surrogate marker for global genomic methylation, which has been reported to associate with disease activity after MTX therapy.
METHODS
We performed a prospective study on 273 naïve early RA (ERA) patients who were treated with MTX, followed up to 12 months, and classified according to their therapy response. The baseline LINE-1 methylation levels in peripheral blood mononuclear cells (PBMC) of cases were assessed by bisulfite pyrosequencing.
RESULTS
Baseline LINE-1 methylation level per se turned out not to predict the response to the therapy, nor did age, sex, body mass index, or smoking status. However, if cases were stratified according to positivity to rheumatoid factor (RF) and anti-citrullinated protein antibody (ACPA) or seronegativity, we observed an opposite association between baseline LINE-1 methylation levels and optimal response to MTX therapy among responders. The best response to MTX therapy was associated with hypermethylated LINE-1 among double-positive ERA cases (-value: 0.002) and with hypomethylated LINE-1 in seronegative ERA patients (-value: 0.01).
CONCLUSION
The LINE-1 methylation level in PBMCs of naïve ERA cases associates with the degree of response to MTX therapy in an opposite way depending on the presence of RF and ACPA antibodies. Our results suggest LINE-1 methylation level as a new epigenetic biomarker for predicting the degree of response to MTX in both double-positive and seronegative ERA patients.
背景
甲氨蝶呤（MTX）被认为是类风湿关节炎（RA）治疗中首选的疾病修饰抗风湿药物（DMARDs）之一。然而，大约有 40%的患者对此没有反应，并且会错过治疗的最佳时间，因此，在开始 MTX 治疗之前拥有一个预测性生物标志物是非常重要的。长散布核元件-1（LINE-1）的甲基化通常被认为是全基因组甲基化的替代标志物，据报道，它与 MTX 治疗后的疾病活动有关。
方法
我们对 273 例接受 MTX 治疗的初治早期 RA（ERA）患者进行了前瞻性研究，随访 12 个月，并根据治疗反应进行分类。通过亚硫酸氢盐焦磷酸测序评估病例外周血单核细胞（PBMC）中 LINE-1 的基础甲基化水平。
结果
LINE-1 基础甲基化水平本身并不能预测治疗反应，年龄、性别、体重指数或吸烟状况也不能预测。然而，如果根据 RF 和抗瓜氨酸蛋白抗体（ACPA）的阳性或阴性对病例进行分层，我们观察到在反应者中，基线 LINE-1 甲基化水平与 MTX 治疗的最佳反应之间存在相反的关联。MTX 治疗的最佳反应与双阳性 ERA 病例中的高甲基化 LINE-1（-值：0.002）和阴性 ERA 患者中的低甲基化 LINE-1（-值：0.01）相关。
结论
初治 ERA 病例 PBMC 中的 LINE-1 甲基化水平与 MTX 治疗反应的程度相关，其方式与 RF 和 ACPA 抗体的存在相反。我们的结果表明，LINE-1 甲基化水平作为一种新的表观遗传生物标志物，可预测双阳性和阴性 ERA 患者对 MTX 治疗反应的程度。
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