DNA methylation is an epigenetic regulator of gene transcription, which has been found to be both metastable and variable within human cohort studies. Currently, few studies have been done to identify metastable DNA methylation biomarkers associated with longitudinal lung function decline in humans. The identification of such biomarkers is important for screening vulnerable populations. We hypothesized that quantifiable blood-based DNA methylation alterations would serve as metastable biomarkers of lung function decline and aging, which may help to discover new pathways and/or mechanisms related to pulmonary pathogenesis. Using linear mixed models, we performed an Epigenome Wide Association Study (EWAS) between DNA methylation at CpG dinucleotides and longitudinal lung function (FVC, FEV1, FEF25–75%) decline and aging with initial discovery in the Normative Aging Study, and replication in the Cooperative Health Research in the Region of Augsburg cohort. We identified two metastable epigenetic loci associated with either poor lung function and aging, cg05575921 (AHRR gene), or lung function independently of aging, cg06126421 (IER3 gene). These loci may inform basic mechanisms associated with pulmonary function, pathogenesis, and aging. Human epigenomic variation, may help explain features of lung function decline and related pathophysiology not attributable to DNA sequence alone, such as accelerated pulmonary decline in smokers, former smokers, and perhaps non-smokers. Our EWAS across two cohorts, therefore, will likely have implications for the human population, not just the elderly.
Funding
This study was funded by the National Institute of Environmental Health Sciences (NIEHS) (R01ES025225; R01ES021733 and R01ES015172). JJC was supported by a Ruth L. Kirschstein National Research Service Award (NRSA) for Individual Postdoctoral Fellows F32ES024068 from the National Institute of Environmental Health Science, National Institutes of Health, and by Training Grant T32ES007069 in Environmental Epidemiology from the National Institute of Environmental Health Science, National Institutes of Health. RTB was funded by R35CA197449, T32GM074897, T32ES007142, and T32CA094880. The US Department of Veterans Affairs (VA) Normative Aging Study (NAS) is supported by the VA Cooperative Studies Program/ERIC, Massachusetts Veterans Epidemiology Research and Information Center (MAVERIC). Additional support to the VA-NAS was provided by the US Department of Agriculture, Agricultural Research Service (contract 53-K06-510). AS3 is supported by a VA Clinical Sciences Research and Development Senior Research Career Scientist award. Funding sources was not involved in study design, collection, analysis and interpretation of data; in the writing of the manuscript; and in the decision to submit the article for publication. KORA work was also supported by the Comprehensive Pneumology Center Munich (CPC-M) as member of the German Center for Lung Research and the Competence Network Asthma and COPD (ASCONET), network COSYCONET (subproject 2, BMBF FKZ 01GI0882) funded by the German “Bundesministerium für Bildung und Forschung” (Federal Ministry of Education and Research, BMBF). The KORA study was initiated and financed by the Helmholtz Zentrum München – German Research Center for Environmental Health, which was funded by the German Federal Ministry of Education and Research (BMBF) and by the State of Bavaria. J.N-E is also supported by a NIH/NIA Ruth L. Kirschstein National Research Service Award (1 F31AG056124-01A1). Work by JNH at the Harvard Chan Bioinformatics Core was part
