Katherine Shutta, PhD
Channing Division of Network Medicine
Katherine H. Shutta*, Yichen Huang, Siqin Li, Brian D. Hobbs, Jeong Yun, Augustine Choi, Edwin K. Silverman, John Quackenbush, Dawn L. DeMeo
Dawn L. DeMeo
Chronic obstructive pulmonary disease (COPD) and pulmonary fibrosis are phenotypically divergent pulmonary disorders related to smoke exposures. Genetic factors have been associated with each disease, but generally have small effect sizes. The relationship between environmental exposures and disease manifestations may relate to epigenetic variability, and DNA methylation may drive the divergence of the lung toward COPD or fibrosis. To investigate this hypothesis, we conducted epigenome-wide association studies (EWAS) in lung tissue to identify distinct and overlapping lung methylation patterns associated with COPD and/or fibrosis. Lung tissue was available from 864 participants in the Lung Tissue Research Consortium (324 controls, 346 cases with COPD, 194 cases with fibrosis). We performed two EWAS: one identifying COPD associations and one identifying fibrosis associations. EWAS models controlled for age, race, sex, smoking status, and cell type composition (estimated with EpiSCORE). 352 probes were significant with FDR < 0.05 in COPD and 31402 were significant in fibrosis, with 52 overlapping probes. Of particular interest, 28 of these demonstrated opposite directions of association, suggesting a possible role as switch probes implicated in the bifurcation of disease progression towards COPD or IPF. 39 KEGG pathways were enriched at FDR < 0.05; top pathways included Rap1 signaling (FDR=3.8e-4), phospholipase D signaling (FDR=0.006), pathways in cancer (FDR=0.007), axon guidance (FDR=0.007), and inflammatory mediator regulation of TRP channels (FDR=0.007). Although no KEGG pathways were significantly enriched in the COPD EWAS, the top pathways found are known to be related to COPD (PPAR signaling, AMPK signaling and ABC transporters). Epigenetic regulation may be a key component of the bifurcation of disease in the lung of smokers toward COPD or fibrosis. Further analysis of the overlapping and distinct epigenetic signals identified in this analysis will provide a new lens for understanding divergent trajectories in lung disease.
Functional evaluation of the enriched pathways and possible switch genes identified in this analysis may reveal new therapeutic targets for obstructive and restrictive lung diseases.