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         <jats:p>To identify interaction networks of airway epithelial cell DNA methylation in COPD and further explore potential correlations with airway bacterial composition, as potentially collective regulators of biological pathways influencing COPD severity.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Using DNA isolated from bronchial airway brushings of 67 ever-smokers (&gt;20 pack-years) from the SubPopulations and InteRmediate Outcomes Measures in COPD Study (SPIROMICS), we assessed proportion of DNA methylation (\u03b2) by epigenome-wide association study (EWAS) and examined associations of differentially methylated CpG probes (DMPs) with risk for moderate-to-severe COPD (N=34) versus absent or mild COPD (N=33). We tested co-methylation modules generated by Weighted Correlation Network Analyses (WGCNA) for associations with moderate-to-severe COPD and with bacterial genus-level relative abundances (16S rRNA sequencing).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      EWAS-identified nominally significant DMPs enriched for lung function GWAS loci. Eigengenes in six WGCNA modules were associated with moderate-to-severe COPD (false discovery rate &lt;0.05). Four of those modules were enriched for forced expiratory volume in 1 s\/forced vital capacity GWAS loci, and five overlapped with DMPs from EWAS. Overlapping CpG loci in three COPD-associated modules were adjacent to mucin genes; one had 10 genes highly ranked by connectivity with\n                      <jats:italic>MUC5B,<\/jats:italic>\n                      including important pathway genes:\n                      <jats:italic>B3GNT6<\/jats:italic>\n                      ,\n                      <jats:italic>DGKI<\/jats:italic>\n                      and\n                      <jats:italic>ITGA8<\/jats:italic>\n                      . CpGs in an independent COPD-associated module showed the most correlations with\n                      <jats:italic>Rothia<\/jats:italic>\n                      , with directionality suggestive of negative associations with moderate-severe COPD.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Bronchial epithelial DNA methylation modules enriched for lung function GWAS loci associate with COPD severity in SPIROMICS. Potential module relationships to bronchial bacterial composition require further validation.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/bmjresp-2025-003572","type":"journal-article","created":{"date-parts":[[2025,12,19]],"date-time":"2025-12-19T04:10:26Z","timestamp":1766117426000},"page":"e003572","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":0,"title":["Epigenomic study of the lower airway reveals COPD-associated methylation patterns and potential microbiota links"],"prefix":"10.1136","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-3414-9616","authenticated-orcid":false,"given":"Shuo","family":"Cao","sequence":"first","affiliation":[{"name":"Mayo Clinic Arizona, Scottsdale, Arizona, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Abhishek","family":"Shrivastav","sequence":"additional","affiliation":[{"name":"Mayo Clinic, Scottsdale, Arizona, 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