Identification of Sjögren’s syndrome patient subgroups by clustering of labial salivary gland DNA methylation profiles

Abstract

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.

Functional significance of DNA methylation: epigenetic insights into Sjögren’s syndrome

“…Cell-specific epigenome-wide analysis showed that genes involved in these pathways are enriched for hypomethylation and hypermethylation at differentially methylated CpG sites (DMCs) ( 103 ). The alteration in the DNA methylation of critical pathways provides a theoretical basis for a therapeutic target in SjS ( Table 2 ) ( 66 , 68 , 75 , 76 , 105 , 107 – 110 , 112 ).…”

“…Further research is required to uncover more details about these interactions and their implications for SjS. Interestingly, besides providing novel therapeutic targets, using DNA methylation arrays in a clinical setting can also advance researchers understanding of classifying SjS phenotype ( 112 ).…”

“…Conversely, IFN-γ-meditated ferroptosis of SGEC exacerbates SjS pathogenesis through JAK/STAT1, signifying the function of ferroptosis in SGECs in SjS-associated immunogenicity and inflammatory responses ( 144 ). Disparity in DNA methylation in salivary gland tissues can exacerbate the progression of autoimmune diseases ( 50 , 112 ). Minor salivary gland-based epigenome-wide DNA methylation found a decreased global DNA methylation in the SGECs from SjS patients.…”

Integrated DNA Methylation and Transcriptomics Analyses of Lacrimal Glands Identify the Potential Genes Implicated in the Development of Sjögren’s Syndrome-Related Dry Eye

“… 12 In a recent paper published in 2023, Chi et al identified two subgroups of SS patients with significantly different DNA methylation levels at the MHC region, based on the genome-wide DNA methylation data from labial salivary gland tissue of SS patients. 13 Although the change of DNA methylation in peripheral blood cells and salivary glands of SS patients has been widely studied, little is known about the DNA methylation profile in LGs as well as the correlation between DNA methylation and disease progression of SS-related dry eye.…”