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Previous published work showed DNA methylation (DNAm) can distinguish SjD case subgroups based on clinical features; however, studies used small samples and did not adjust for cellular heterogeneity in labial salivary glands (LSGs). Our objectives were to: (1) identify DNAm clusters from LSGs; (2) investigate cluster clinical characteristics; and (3) identify differential methylation between SjD case subgroups to further understand biological pathways.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We identified clinically meaningful subgroups of SjD through hierarchical clustering of DNAm embeddings from a variational autoencoder (VAE) of LSGs, which allows for a low dimensional representation of the high dimensional methylation data. LSGs from\u00a01,059 individuals, SjD cases (\n                      <jats:italic>n<\/jats:italic>\n                      \u2009=\u2009592) and symptomatic non-cases (\n                      <jats:italic>n<\/jats:italic>\n                      \u2009=\u2009467) were profiled using the Illumina HumanMethylationEPIC BeadChip, and cell-type proportions were estimated using a solid-tissue reference.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Participants clustered into subgroups with differential SjD features and proportions of predicted cell-types. Comparison of SjD cases within distinct clusters showed evidence for differential methylation in each cell-type. The largest number of differences between subgroups occurred in epithelial and B-cells and were in genes and pathways with relevance to disease pathogenesis. In B-cells, methylation within\n                      <jats:italic>NR2F2<\/jats:italic>\n                      , previously reported to be differentially expressed in lacrimal glands of SjD mouse models, and\n                      <jats:italic>NDRG2<\/jats:italic>\n                      , which increases saliva production in estrogen deficient rats, distinguished subgroups with different clinical manifestations. Additional candidates of interest identified in epithelial and B-cells from SjD cases include genes previously implicated in systemic lupus erythematosus.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>These findings provide insight into the powerful link between epigenetics and clinical heterogeneity in SjD and contribute to classification of important patient subgroups.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s13075-026-03744-7","type":"journal-article","created":{"date-parts":[[2026,2,4]],"date-time":"2026-02-04T03:08:56Z","timestamp":1770174536000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Sj\u00f6gren\u2019s patient subgroups identified through whole genome DNA methylation profiling"],"prefix":"10.1186","volume":"28","author":[{"given":"Olivia","family":"Solomon","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caroline","family":"Shiboski","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kimberly E.","family":"Taylor","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hong","family":"Quach","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diana","family":"Quach","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lisa F.","family":"Barcellos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lindsey A.","family":"Criswell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,2,4]]},"reference":[{"key":"3744_CR1","doi-asserted-by":"publisher","first-page":"1347","DOI":"10.1002\/art.41676","volume":"73","author":"AN Baer","year":"2021","unstructured":"Baer AN, Hammitt KM. 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