Metastable DNA methylation sites associated with longitudinal lung function decline and aging in humans: an epigenome-wide study in the NAS and KORA cohorts

Juan Jose Carmona; Richard T. Barfield; Tommaso Panni; Jamaji C. Nwanaji-Enwerem; Allan C. Just; John N. Hutchinson; Elena Colicino; Stefan Karrasch; Simone Wahl; Sonja Kunze; Nadereh Jafari; Yinan Zheng; Lifang Hou; Dawn L. DeMeo; Augusto A. Litonjua; Pantel S. Vokonas; Annette Peters; Xihong Lin; Joel Schwartz; Holger Schulz; Andrea A. Baccarelli

doi:10.1080/15592294.2018.1529849

Metastable DNA methylation sites associated with longitudinal lung function decline and aging in humans: an epigenome-wide study in the NAS and KORA cohorts

Juan Jose Carmona, Richard T. Barfield^*, Tommaso Panni, Jamaji C. Nwanaji-Enwerem, Allan C. Just, John N. Hutchinson, Elena Colicino, Stefan Karrasch, Simone Wahl, Sonja Kunze, Nadereh Jafari, Yinan Zheng, Lifang Hou, Dawn L. DeMeo, Augusto A. Litonjua, Pantel S. Vokonas, Annette Peters, Xihong Lin, Joel Schwartz, Holger SchulzAndrea A. Baccarelli

^*Corresponding author for this work

Preventive Medicine

Research output: Contribution to journal › Article › peer-review

19 Scopus citations

Abstract

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, FEV ₁ , FEF _25–75% ) 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.

Original language	English (US)
Pages (from-to)	1039-1055
Number of pages	17
Journal	Epigenetics
Volume	13
Issue number	10-11
DOIs	https://doi.org/10.1080/15592294.2018.1529849
State	Published - Nov 2 2018

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 partly supported by Award Number P30 ES00002 from the National Institute of Environmental Health Sciences. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Environmental Health Sciences or the National Institutes of Health. 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 partly supported by Award Number P30 ES00002 from the National Institute of Environmental Health Sciences. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Environmental Health Sciences or the National Institutes of Health. We thank all of the human participants involved in both the NAS and KORA cohorts: we are grateful for their participation and cooperation. We also thank the clinical staff and scientific teams associated with these cohorts based in the USA and Germany for their excellent care of all participants. The NAS computations in this paper were run on the Odyssey cluster supported by the FAS Division of Science, Research Computing Group at Harvard University. Lastly, we also thank the Genomics Core Facility at Northwestern University for their technical assistance regarding the Infinium HumanMethylation450K BeadChip technology.

Keywords

Biomarker
DNA methylation
lung function decline
pulmonary function

ASJC Scopus subject areas

Molecular Biology
Cancer Research

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10.1080/15592294.2018.1529849

Cite this

Carmona, J. J., Barfield, R. T., Panni, T., Nwanaji-Enwerem, J. C., Just, A. C., Hutchinson, J. N., Colicino, E., Karrasch, S., Wahl, S., Kunze, S., Jafari, N., Zheng, Y., Hou, L., DeMeo, D. L., Litonjua, A. A., Vokonas, P. S., Peters, A., Lin, X., Schwartz, J., ... Baccarelli, A. A. (2018). Metastable DNA methylation sites associated with longitudinal lung function decline and aging in humans: an epigenome-wide study in the NAS and KORA cohorts. Epigenetics, 13(10-11), 1039-1055. https://doi.org/10.1080/15592294.2018.1529849

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title = "Metastable DNA methylation sites associated with longitudinal lung function decline and aging in humans: an epigenome-wide study in the NAS and KORA cohorts",

abstract = " 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, FEV 1 , FEF 25–75\% ) 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.",

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Carmona, JJ, Barfield, RT, Panni, T, Nwanaji-Enwerem, JC, Just, AC, Hutchinson, JN, Colicino, E, Karrasch, S, Wahl, S, Kunze, S, Jafari, N, Zheng, Y , Hou, L, DeMeo, DL, Litonjua, AA, Vokonas, PS, Peters, A, Lin, X, Schwartz, J, Schulz, H & Baccarelli, AA 2018, 'Metastable DNA methylation sites associated with longitudinal lung function decline and aging in humans: an epigenome-wide study in the NAS and KORA cohorts', Epigenetics, vol. 13, no. 10-11, pp. 1039-1055. https://doi.org/10.1080/15592294.2018.1529849

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AU - Carmona, Juan Jose

AU - Barfield, Richard T.

AU - Panni, Tommaso

AU - Nwanaji-Enwerem, Jamaji C.

AU - Just, Allan C.

AU - Hutchinson, John N.

AU - Colicino, Elena

AU - Karrasch, Stefan

AU - Wahl, Simone

AU - Kunze, Sonja

AU - Jafari, Nadereh

AU - Zheng, Yinan

AU - Hou, Lifang

AU - DeMeo, Dawn L.

AU - Litonjua, Augusto A.

AU - Vokonas, Pantel S.

AU - Peters, Annette

AU - Lin, Xihong

AU - Schwartz, Joel

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Metastable DNA methylation sites associated with longitudinal lung function decline and aging in humans: an epigenome-wide study in the NAS and KORA cohorts

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