Clinical phenotype analysis by cluster.

Heterogeneity in Sjögren’s syndrome (SS), increasingly called Sjögren’s disease, suggests the presence of disease subtypes, which poses a major challenge for the diagnosis, management, and treatment of this autoimmune disorder. Previous work distinguished patient subgroups based on clinical symptoms, but it is not clear to what extent symptoms reflect underlying pathobiology. The purpose of this study was to discover clinical meaningful subtypes of SS based on genome-wide DNA methylation data. We performed a cluster analysis of genome-wide DNA methylation data from labial salivary gland (LSG) tissue collected from 64 SS cases and 67 non-cases. Specifically, hierarchical clustering was performed on low dimensional embeddings of DNA methylation data extracted from a variational autoencoder to uncover unknown heterogeneity. Clustering revealed clinically severe and mild subgroups of SS. Differential methylation analysis revealed that hypomethylation at the MHC and hypermethylation at other genome regions characterize the epigenetic differences between these SS subgroups. Epigenetic profiling of LSGs in SS yields new insights into mechanisms underlying disease heterogeneity. The methylation patterns at differentially methylated CpGs are different in SS subgroups and support the role of epigenetic contributions to the heterogeneity in SS. Biomarker data derived from epigenetic profiling could be explored in future iterations of the classification criteria for defining SS subgroups.

干燥综合征（Sjögren’s syndrome, SS，如今越来越多地被称为干燥综合征疾病）的异质性提示存在疾病亚型，这给该自身免疫性疾病的诊断、管理与治疗带来了重大挑战。既往研究基于临床症状对患者亚群进行了区分，但尚不清楚症状在多大程度上能够反映潜在的病理生物学机制。本研究旨在基于全基因组DNA甲基化数据（genome-wide DNA methylation data），挖掘具有临床意义的SS亚群。我们对64例SS患者与67例非患者的唇腺（labial salivary gland, LSG）组织的全基因组DNA甲基化数据开展了聚类分析。具体而言，我们对从变分自编码器（variational autoencoder）中提取的DNA甲基化数据低维嵌入进行层次聚类，以揭示未知的疾病异质性。聚类分析结果显示，SS存在临床严重型与轻症型两个亚群。差异甲基化分析表明，MHC（主要组织相容性复合体）区域的低甲基化与其他基因组区域的高甲基化，是这两个SS亚群之间表观遗传差异的特征。对SS患者唇腺的表观遗传谱分析，为疾病异质性的潜在机制提供了新的见解。差异甲基化CpG位点的甲基化模式在SS亚群中存在显著差异，这支持了表观遗传调控在SS异质性形成中的作用。未来在修订SS亚群分类标准时，可以探索利用从表观遗传谱分析中获得的生物标志物数据。