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While MD immune response has been linked to autoinflammation and type 2 cytokines, other molecular mechanisms such as DNA methylation have an emerging yet underexplored role in MD pathophysiology.To understand the role of DNA methylation in MD, we performed whole-genome bisulphite sequencing in MD patients (<jats:italic>n<\/jats:italic>\u2009=\u200940) and controls (<jats:italic>n<\/jats:italic>\u2009=\u200913) and used differentially methylated cytosines (DMCs) to define clusters, cell types, and biochemical pathways in MD. We found three MD subclusters: Cluster 1 (40% of patients) and Cluster 3 (25%) showed DMC profiles against controls, while Cluster 2 (35%) did not. Significant DMCs from Cluster 1 and Cluster 3 versus Control analysis were annotated to 3033 and 59 unique genes, respectively. Each cluster showed a different gene enrichment; however, the <jats:italic>KDMB4<\/jats:italic> gene had significant upregulated DNA accessibility in a complementary ATAC-seq dataset and showed significant DMCs in both Cluster 1 and Cluster 3. DNA methylation patterns in MD reveal three clusters which are reflective of an underlying difference in pathways related to cytokine stimulus, immunity T-cell, and NK-cell pathways. <jats:italic>KDMB4<\/jats:italic> emerges as a critical MD gene which deserves further research.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Key messages<\/jats:title>\n            <jats:p>\n              <jats:list list-type=\"bullet\">\n                <jats:list-item>\n                  <jats:p>We asked if DNA methylation can help understand Meniere\u2019s Disease (MD) pathophysiology.<\/jats:p>\n                <\/jats:list-item>\n                <jats:list-item>\n                  <jats:p>DNA methylomes group MD patients into three distinct sub-clusters.<\/jats:p>\n                <\/jats:list-item>\n                <jats:list-item>\n                  <jats:p>DNA methylation in MD reflect difference in pathways related to neurons and cytokine stimulus.<\/jats:p>\n                <\/jats:list-item>\n                <jats:list-item>\n                  <jats:p>The data shows <jats:italic>KDMB4<\/jats:italic> emerging as a key gene that requires further multi-modal investigation.<\/jats:p>\n                <\/jats:list-item>\n              <\/jats:list>\n            <\/jats:p>\n          <\/jats:sec>","DOI":"10.1007\/s00109-025-02581-6","type":"journal-article","created":{"date-parts":[[2025,8,6]],"date-time":"2025-08-06T08:01:36Z","timestamp":1754467296000},"page":"1191-1204","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Whole genome DNA methylation profiles define Meniere\u2019s disease subclusters"],"prefix":"10.1007","volume":"103","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8628-2795","authenticated-orcid":false,"given":"Vibha","family":"Patil","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-1699-3617","authenticated-orcid":false,"given":"Pablo","family":"Cruz-Granados","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francisca E.","family":"Cara","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9749-8607","authenticated-orcid":false,"given":"Juan Carlos","family":"Amor-Dorado","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0753-6380","authenticated-orcid":false,"given":"Ismael","family":"Aran","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andres","family":"Soto-Varela","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2722-4947","authenticated-orcid":false,"given":"Patricia","family":"Perez-Carpena","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8583-1430","authenticated-orcid":false,"given":"Jose Antonio","family":"Lopez-Escamez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,8,6]]},"reference":[{"issue":"1","key":"2581_CR1","doi-asserted-by":"publisher","first-page":"138","DOI":"10.1055\/s-0039-3402065","volume":"40","author":"P Perez-Carpena","year":"2020","unstructured":"Perez-Carpena P, Lopez-Escamez JA (2020) Current understanding and clinical management of Meniere\u2019s disease: a systematic review. 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