Journal article
Epigenomic study of the lower airway reveals COPD-associated methylation patterns and potential microbiota links
BMJ open respiratory research, Vol.12(1), e003572
12/18/2025
DOI: 10.1136/bmjresp-2025-003572
PMCID: PMC12716595
PMID: 41419234
Abstract
Introduction Despite the identification of multiple susceptibility loci by genome-wide association studies (GWAS), considerable chronic obstructive pulmonary disease (COPD) heritability remains unexplained.
Aim 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.
Methods Using DNA isolated from bronchial airway brushings of 67 ever-smokers (>20 pack-years) from the SubPopulations and InteRmediate Outcomes Measures in COPD Study (SPIROMICS), we assessed proportion of DNA methylation (β) 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).
Results 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 <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 MUC5B, including important pathway genes: B3GNT6, DGKI and ITGA8. CpGs in an independent COPD-associated module showed the most correlations with Rothia, with directionality suggestive of negative associations with moderate-severe COPD.
Conclusions 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.
Details
- Title: Subtitle
- Epigenomic study of the lower airway reveals COPD-associated methylation patterns and potential microbiota links
- Creators
- Shuo CaoAbhishek Shrivastav - Mayo Clinic in ArizonaEugene R Bleecker - Mayo Clinic in ArizonaSiddharth Madapoosi - University of MichiganJohn Erb-Downward - University of MichiganJoe Zein - Mayo Clinic in ArizonaXianfeng Chen - Mayo Clinic in ArizonaTimothy D Howard - Wake Forest UniversityGregory A Hawkins - Wake Forest UniversityIgor Z Barjaktarevic - University of California, Los AngelesRussell Bowler - Cleveland ClinicRobert Graham Barr - Columbia University Irving Medical CenterAlejandro Comellas - University of IowaChristopher B Cooper - University of California, Los AngelesDavid Couper - University of North Carolina at Chapel HillMeilan Han - University of MichiganNadia N Hansel - Johns Hopkins UniversityAnnette T Hastie - Wake Forest UniversityRobert Kaner - Cornell UniversityRichard E Kanner - University of UtahVictor Kim - Temple UniversityFernando J Martinez - University of Massachusetts Chan Medical SchoolWendy C Moore - Wake Forest UniversityWanda K O'NealRobert Paine - University of UtahBenjamin Smith - Columbia UniversityEric A Hoffman - University of Iowa, RadiologyDeborah A Meyers - Mayo Clinic in ArizonaPrescott G Woodruff - University of California, San FranciscoStephanie Christenson - University of California, San FranciscoJeffrey L Curtis - University of MichiganYvonne Jean Huang - University of MichiganVictor E Ortega - Mayo Clinic in Arizona
- Resource Type
- Journal article
- Publication Details
- BMJ open respiratory research, Vol.12(1), e003572
- DOI
- 10.1136/bmjresp-2025-003572
- PMID
- 41419234
- PMCID
- PMC12716595
- NLM abbreviation
- BMJ Open Respir Res
- ISSN
- 2052-4439
- eISSN
- 2052-4439
- Publisher
- BMJ Publishing Group
- Grant note
- GlaxoSmithKline: supplemented by contributions Amgen: supplemented by contributions Forest Research Institute: supplemented by contributions NIH/NHLBI: HHSN268200900013C, HHSN268200900014C, HHSN268200900015C, HHSN268200900016C, HHSN268200900017C, HHSN268200900018C, HHSN268200900019C, HHSN268200900020C, R01 HL142992, R01 HL144718, R01 HL182622, U01 HL137880, U24 HL141762 Chiesi Farmaceutici: supplemented by contributions Bayer: supplemented by contributions Ikaria: supplemented by contributions Regeneron Pharmaceuticals: supplemented by contributions Theravance Biopharma: supplemented by contributions Novartis Pharmaceuticals Corporation: supplemented by contributions Genentech: supplemented by contributions Grifols: supplemented by contributions Takeda Pharmaceutical Company: supplemented by contributions Bellerophon Therapeutics: supplemented by contributions Sunovion: supplemented by contributions Boehringer Ingelheim: supplemented by contributions ProterixBio: supplemented by contributions Mylan: supplemented by contributions AstraZeneca: supplemented by contributions MGC Diagnostics: supplemented by contributions Polarean: supplemented by contributions Nycomed GmbH: supplemented by contributions Sanofi: supplemented by contributions
SPIROMICS was supported by contracts from the NIH/NHLBI (HHSN268200900013C, HHSN268200900014C, HHSN268200900015C, HHSN268200900016C, HHSN268200900017C, HHSN268200900018C, HHSN268200900019C, HHSN268200900020C), grants from the NIH/NHLBI (U01 HL137880, U24 HL141762, R01 HL182622 and R01 HL144718 and R01 HL142992), and supplemented by contributions made through the Foundation for the NIH and the COPD Foundation from Amgen; AstraZeneca/MedImmune; Bayer; Bellerophon Therapeutics; Boehringer-Ingelheim Pharmaceuticals; Chiesi Farmaceutici S.p.A.; Forest Research Institute; Genentech; GlaxoSmithKline; Grifols Therapeutics; Ikaria; MGC Diagnostics; Novartis Pharmaceuticals Corporation; Nycomed; Polarean; ProterixBio; Regeneron Pharmaceuticals; Sanofi; Sunovion; Takeda Pharmaceutical Company and Theravance Biopharma and Mylan/Viatris. VEO, MD, PhD, ATSF; YJH, MD, ATSF, FAAAAI; and SCa had full access to all the data in the study and had final responsibility for the decision to submit for publication.
- Language
- English
- Date published
- 12/18/2025
- Academic Unit
- Roy J. Carver Department of Biomedical Engineering; Radiology; Pulmonary, Critical Care, and Occupational Medicine; ICTS; Internal Medicine
- Record Identifier
- 9985090588802771
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