Horton Mary K, Nititham Joanne, Taylor Kimberly E, Katz Patricia, Ye Chun Jimmie, Yazdany Jinoos, Dall'Era Maria, Hurabielle Charlotte, Barcellos Lisa F, Criswell Lindsey A, Lanata Cristina M
Genomics of Autoimmune Rheumatic Disease Section, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
Division of Rheumatology, Department of Medicine, University of California San Francisco, San Francisco, CA, USA.
Clin Epigenetics. 2024 Dec 18;16(1):181. doi: 10.1186/s13148-024-01792-x.
Systemic lupus erythematosus (SLE) has numerous symptoms across organs and an unpredictable flare-remittance pattern. This has made it challenging to understand drivers of long-term SLE outcomes. Our objective was to identify whether changes in DNA methylation over time, in an actively flaring SLE cohort, were associated with remission and whether these changes meaningfully subtype SLE patients.
Fifty-nine multi-ethnic SLE patients had clinical visits and DNA methylation profiles at a flare and approximately 3 months later. Methylation was measured using the Illumina EPIC array. We identified sites where methylation change between visits was associated with remission at the follow-up visit using limma package and a time x remission interaction term. Models adjusted for batch, age at diagnosis, time between visits, age at flare, sex, medications, and cell-type proportions. Separately, a paired T-test identified Bonferroni significant methylation sites with ≥ 3% change between visits (n = 546). Methylation changes at these sites were used for unsupervised consensus hierarchical clustering. Associations between clusters and patient features were assessed.
Nineteen patients fully remitted at the follow-up visit. For 1,953 CpG sites, methylation changed differently for remitters vs. non-remitters (Bonferroni p < 0.05). Nearly half were within genes regulated by interferon. The largest effect was at cg22873177; on average, remitters had 23% decreased methylation between visits while non-remitters had no change. Three SLE patient clusters were identified using methylation differences agnostic of clinical outcomes. All Cluster 1 subjects (n = 12) experienced complete flare remission, despite similar baseline disease activity scores, medications, and demographics as other clusters. Methylation changes at six CpG sites, including within immune-related CD45 and IFI genes, were particularly distinct for each cluster, suggesting these may be good candidates for stratifying patients in the future.
Changes in DNA methylation during active SLE were associated with remission status and identified subgroups of SLE patients with several distinct clinical and biological characteristics. DNA methylation patterns might help inform SLE subtypes, leading to targeted therapies based on relevant underlying biological pathways.
系统性红斑狼疮（SLE）累及多个器官，症状繁多，病情缓解-复发模式不可预测。这使得了解SLE长期预后的驱动因素具有挑战性。我们的目标是确定在一个处于疾病活动期的SLE队列中，DNA甲基化随时间的变化是否与病情缓解相关，以及这些变化是否能对SLE患者进行有意义的亚型分类。
59名多民族SLE患者在疾病活动期及大约3个月后进行了临床访视并检测了DNA甲基化谱。使用Illumina EPIC芯片检测甲基化。我们使用limma软件包和时间×缓解交互项，确定了访视间甲基化变化与随访时病情缓解相关的位点。模型对批次、诊断时年龄、访视间隔时间、疾病活动期年龄、性别、药物治疗和细胞类型比例进行了校正。另外，配对T检验确定了访视间变化≥3%的Bonferroni显著甲基化位点（n = 546）。这些位点的甲基化变化用于无监督一致性层次聚类。评估聚类与患者特征之间的关联。
19名患者在随访时完全缓解。对于1953个CpG位点，缓解者与未缓解者的甲基化变化不同（Bonferroni p < 0.05）。其中近一半位于受干扰素调控的基因内。影响最大的是cg22873177；平均而言，缓解者访视间甲基化降低了23%，而未缓解者没有变化。利用与临床结局无关的甲基化差异，确定了三个SLE患者聚类。尽管第1组所有受试者（n = 12）的基线疾病活动评分、药物治疗和人口统计学特征与其他组相似，但他们均实现了疾病完全缓解。六个CpG位点的甲基化变化，包括免疫相关的CD45和IFI基因内的变化，在每个聚类中尤为明显，这表明这些位点可能是未来对患者进行分层的良好候选指标。
活动期SLE患者的DNA甲基化变化与缓解状态相关，并确定了具有几种不同临床和生物学特征的SLE患者亚组。DNA甲基化模式可能有助于明确SLE亚型，从而基于相关潜在生物学途径进行靶向治疗。
