Abstract
Previous reports link differential DNA methylation (DNAme) to environmental exposures which are associated with lung function. Direct evidence on lung function DNAme is however limited. We undertook an agnostic epigenome-wide association study (EWAS) on pre-bronchodilation lung function and its change in adults.
In a discovery-replication EWAS design, DNAme in blood and spirometry were measured twice, six-to-15 years apart, in the same participants of three adult population-based discovery cohorts (n=2043). Associated DNAme markers (p<5×10−7) were tested in seven replication cohorts (adult: n=3327; childhood: n=420). Technical-bias adjusted residuals of a regression of the normalised absolute beta-values on control-probe-derived principle components were regressed on level and change of FEV1, FEV1/FVC and FVC in covariate-adjusted discovery EWAS. Inverse-variance weighted meta-analyses were performed on results from discovery and replication samples in all participants and never smokers.
EWAS signals were enriched for smoking-related DNAme. We replicated 57 lung function DNAme in adult, but not childhood samples, all previously associated with smoking. Markers not previously associated with smoking failed replication. cg05575921 (AHRR) showed the statistically most significant association with cross-sectional lung function (FEV1/FVC: Pdiscovery=3.96×10−21 and Pcombined=7.22×10−50). A score combining ten DNAme markers previously reported to mediate the smoking effect on lung function was associated with lung function (FEV1/FVC: p=2.65×10−20).
Our results reveal that lung function associated methylation signals in adults are predominantly smoking-related and possibly of clinical utility in identifying poor lung function and accelerated decline. Larger studies with more repeat time points are needed to identify lung function DNAme in never smokers and in children.
Footnotes
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Conflict of interest: Dr. Imboden has nothing to disclose.
Conflict of interest: Dr. Wielscher has nothing to disclose.
Conflict of interest: Dr. Rezwan has nothing to disclose.
Conflict of interest: Dr. Amaral has nothing to disclose.
Conflict of interest: Dr. Schaffner has nothing to disclose.
Conflict of interest: Dr. Jeong has nothing to disclose.
Conflict of interest: Dr. Beckmeyer-Borowko has nothing to disclose.
Conflict of interest: Dr. Harris reports grants from Medical Research Council, grants from Biotechnology and Biological Sciences Research Council, grants from Age UK, grants from The Wellcome Trust, during the conduct of the study.
Conflict of interest: Dr. Starr has nothing to disclose.
Conflict of interest: Dr. Deary reports grants from Age UK, grants from Medical Research Council, during the conduct of the study.
Conflict of interest: Dr. Flexeder has nothing to disclose.
Conflict of interest: Dr. Waldenberger has nothing to disclose.
Conflict of interest: Dr. Peters has nothing to disclose.
Conflict of interest: Dr. Schulz reports grants from Competence Network Asthma and COPD (ASCONET), network COSYCONET, grants from Comprehensive Pneumology Center Munich (CPC-M), German Center for Lung Research (DZL), during the conduct of the study.
Conflict of interest: Dr. CHEN has nothing to disclose.
Conflict of interest: Dr. Sunny has nothing to disclose.
Conflict of interest: Dr. Karmaus has nothing to disclose.
Conflict of interest: Dr. Jiang has nothing to disclose.
Conflict of interest: Erhart has nothing to disclose.
Conflict of interest: Dr. Kronenberg has nothing to disclose.
Conflict of interest: Dr. Arathimos has nothing to disclose.
Conflict of interest: Dr. Sharp has nothing to disclose.
Conflict of interest: Dr. Henderson reports grants from Medical Research Council, grants from Wellcome Trust, during the conduct of the study.
Conflict of interest: Dr. Fu has nothing to disclose.
Conflict of interest: Päivi Piirilä has no conflicts of interests to the manuscript of Medea Imboden et al.
Conflict of interest: Dr. Pietiläinen has nothing to disclose.
Conflict of interest: Dr. Ollikainen has nothing to disclose.
Conflict of interest: Dr. Johansson has nothing to disclose.
Conflict of interest: Dr. Gyllensten has nothing to disclose.
Conflict of interest: Dr. de Vries has nothing to disclose.
Conflict of interest: Dr. van der Plaat has nothing to disclose.
Conflict of interest: Dr. de Jong has nothing to disclose.
Conflict of interest: Dr. Boezen has nothing to disclose.
Conflict of interest: Dr. Hall reports grants from GSK, grants from Boehringer Ingelheim, outside the submitted work.
Conflict of interest: Dr. Tobin reports grants from Research collaboration with Pfizer, grants from Research collaboration with GSK, outside the submitted work.
Conflict of interest: Dr. Jarvelin has nothing to disclose.
Conflict of interest: Dr. Holloway reports grants from European Union, grants from National Institutes of Health, during the conduct of the study.
Conflict of interest: Prof. Jarvis reports grants from EU, grants from Medical research council, grants from Asthma UK, during the conduct of the study.
Conflict of interest: Dr. Probst-Hensch has nothing to disclose.
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