Systemic steroid exposure is associated with differential methylation in chronic obstructive pulmonary disease.
BACKGROUND
Systemic glucocorticoids are used therapeutically to treat a variety of medical conditions. Epigenetic processes such as DNA methylation may reflect exposure to glucocorticoids and may be involved in mediating the responses and side effects associated with these medications.


OBJECTIVE
To test the hypothesis that differences in DNA methylation are associated with current systemic steroid use.


METHODS
We obtained DNA methylation data at 27,578 CpG sites in 14,475 genes throughout the genome in two large, independent cohorts: the International COPD Genetics Network (n(discovery) = 1,085) and the Boston Early Onset COPD study (n(replication) = 369). Sites were tested for association with current systemic steroid use using generalized linear mixed models.


RESULTS
A total of 511 sites demonstrated significant differential methylation by systemic corticosteroid use in all three of our primary models. Pyrosequencing validation confirmed robust differential methylation at CpG sites annotated to genes such as SLC22A18, LRP3, HIPK3, SCNN1A, FXYD1, IRF7, AZU1, SIT1, GPR97, ABHD16B, and RABGEF1. Functional annotation clustering demonstrated significant enrichment in intrinsic membrane components, hemostasis and coagulation, cellular ion homeostasis, leukocyte and lymphocyte activation and chemotaxis, protein transport, and responses to nutrients.


CONCLUSIONS
Our analyses suggest that systemic steroid use is associated with site-specific differential methylation throughout the genome. Differentially methylated CpG sites were found in biologically plausible and previously unsuspected pathways; these genes and pathways may be relevant in the development of novel targeted therapies.
Channing Division of Network Medicine, Brigham and Women’s Hospital, Boston, Massachusetts, USA. reesw@channing.harvard.edu
Emily S
ES
Wan
Weiliang
W
Qiu
Andrea
A
Baccarelli
Vincent J
VJ
Carey
Helene
H
Bacherman
Stephen I
SI
Rennard
Alvar
A
Agustí
Wayne H
WH
Anderson
David A
DA
Lomas
Dawn L
DL
DeMeo
D018899:CpG Islands / Q000235:genetics; D019175:DNA Methylation / Q000187:drug effects*; D044127:Epigenesis, Genetic / Q000187:drug effects*; D005190:Family; D005260:Female; D005541:Forced Expiratory Volume; D015894:Genome, Human; D005938:Glucocorticoids / Q000009:adverse effects* / Q000235:genetics / Q000627:therapeutic use; D006801:Humans; D008297:Male; D008875:Middle Aged; D029424:Pulmonary Disease, Chronic Obstructive / Q000188:drug therapy* / Q000235:genetics / Q000503:physiopathology; D012907:Smoking / Q000009:adverse effects; D014797:Vital Capacity
D005938:Glucocorticoids