University of Oulu

Beckmeyer-Borowko, A., Imboden, M., Rezwan, F., Wielscher, M., Amaral, A., Jeong, A., Schaffner, E., Auvinen, J., Sebert, S., Karhunen, V., Bettschart, R., Turk, A., Pons, M., Stolz, D., Kronenberg, F., Arathimos, R., Sharp, G., Relton, C., Henderson, A., Jarvelin, M., Jarvis, D., Holloway, J., Probst-Hensch, N. (2018) SERPINA1 methylation and lung function in tobacco-smoke exposed European children and adults: a meta-analysis of ALEC population-based cohorts. Respiratory Research, 19, 156.

SERPINA1 methylation and lung function in tobacco-smoke exposed European children and adults : a meta-analysis of ALEC population-based cohorts

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Author: Beckmeyer-Borowko, Anna1,2; Imboden, Medea1,2; Rezwan, Faisal I.3;
Organizations: 1Swiss Tropical and Public Health Institute, Socinstrasse 57, 4002 Basel, Switzerland
2University of Basel, Basel, Switzerland
3Human Development and Health, Faculty of Medicine, University of Southampton, Southampton, UK
4Department of Epidemiology and Biostatistics, MRC-PHE Centre for Environment and Health, School of Public Health, Imperial College London, W2 1PG, London, UK
5Population Health and Occupational Disease, NHLI, Imperial College London, London, UK
6Center for Life Course Health Research, University of Oulu, Oulu, Finland
7Oulunkaari Health Center, Ii, Finland
8Medical Research Center, University Hospital of Oulu, University of Oulu, Oulu, Finland
9Biocenter Oulu, University of Oulu, Oulu, Finland
10Department for Genomics of Common Diseases, School of Public Health, Imperial College London, London, UK
11Lungenpraxis Aarau, Hirslanden Klinik, Aarau, Switzerland
12Zürcher Höhenklinik, Wald, Switzerland
13Ospedale Regionale di Lugano-Sede Civico, Lugano, Switzerland
14Clinic of Pulmonary Medicine and Respiratory Cell Research, Basel, Switzerland
15Division of Genetic Epidemiology, Department of Medical Genetics, Molecular and Clinical Pharmacology, Innsbruck Medical University, Innsbruck, Austria
16MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK
17Department of Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK
18Bristol Dental School, University of Bristol, Bristol, UK
19Unit of Primary Health Care, Oulu University Hospital, OYS, Kajaanintie 50, 90220 Oulu, Finland
20Department of Life Sciences, College of Health and Life Sciences, Brunel University London, Kingston Lane, Uxbridge, Middlesex, UB8 3PH, UK
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 1.2 MB)
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Language: English
Published: Springer Nature, 2018
Publish Date: 2019-05-06


Background: The pathophysiological role of SERPINA1 in respiratory health may be more strongly determined by the regulation of its expression than by common genetic variants. A family based study of predominantly smoking adults found methylation at two Cytosine-phosphate-Guanine sites (CpGs) in SERPINA1 gene to be associated with chronic obstructive pulmonary disease risk. The objective of this study was to confirm the association of lung function with SERPINA1 methylation in general population samples by testing a comprehensive set of CpGs in the SERPINA gene cluster. We considered lung function level and decline in adult smokers from three European population-based cohorts and lung function level and growth in tobacco-smoke exposed children from a birth cohort.

Methods: DNA methylation using Illumina Infinium Human Methylation 450 k and EPIC beadchips and lung function were measured at two time points in 1076 SAPALDIA, ECRHS and NFBC adult cohort participants and 259 ALSPAC children. Associations of methylation at 119 CpG sites in the SERPINA gene cluster (PP4R4-SERPINA13P) with lung functions and circulating alpha-1-antitripsin (AAT) were assessed using multivariable cross-sectional and longitudinal regression models.

Results: Methylation at cg08257009 in the SERPINA gene cluster, located 32 kb downstream of SERPINA1, not annotated to a gene, was associated with FEV1/FVC at the Bonferroni corrected level in adults, but not in children. None of the methylation signals in the SERPINA1 gene showed associations with lung function after correcting for multiple testing.

Conclusions: The results do not support a role of SERPINA1 gene methylation as determinant of lung function across the life course in the tobacco smoke exposed general population exposed.

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Series: Respiratory research
ISSN: 1465-9921
ISSN-E: 1465-9921
ISSN-L: 1465-9921
Volume: 19
Article number: 156
DOI: 10.1186/s12931-018-0850-8
Type of Publication: A1 Journal article – refereed
Field of Science: 3121 General medicine, internal medicine and other clinical medicine
3141 Health care science
Funding: The ALEC Study is funded by the European Union’s Horizon 2020 Research and Innovation programme under grant agreement No. 633212. [...] The SAPALDIA Cohort is funded by the Swiss National Science Foundation (grants no 33CS30–148470/1&2, 33CSCO-134276/1, 33CSCO-108796,, 324730_135673, 3247BO-104283, 3247BO-104288, 3247BO-104284, 3247–065896, 3100–059302, 3200–052720, 3200–042532, 4026–028099, PMPDP3_129021/1, PMPDP3_141671/1), the Federal Office for the Environment, the Federal Office of Public Health, the Federal Office of Roads and Transport, the canton’s government of Aargau, Basel-Stadt, Basel-Land, Geneva, Luzern, Ticino, Valais, and Zürich, the Swiss Lung League, the canton’s Lung League of Basel Stadt/ Basel Landschaft, Geneva, Ticino, Valais, Graubünden and Zurich, Stiftung ehemals Bündner Heilstätten, SUVA, Freiwillige Akademische Gesellschaft, UBS Wealth Foundation, Talecris Biotherapeutics GmbH, Abbott Diagnostics, Klinik Barmelweid, Hirslanden Klinik Aarau, European Commission 018996 (GABRIEL), Wellcome Trust WT 084703MA, Exposomics EC FP7 grant(Grant agreement No: 308610). The ECRHS cohort was supported by France: Ministère de la Santé, Glaxo France, Insitut Pneumologique d’Aquitaine, Contrat de Plan Etat-Région Languedoc-Rousillon, CNMATS, CNMRT (90MR/10, 91AF/6), Ministre Délégué de la Santé, RNSP, GSF, and Programme Hospitalier de Recherche Clinique National 2010. France (Grenoble): Direction de la Recherche Clinique de Grenoble 2000 (no. 2610), Ministère de l’Emploi et de la Solidarité, Direction Générale de la Sante, CHU Grenoble, Comite des Maladies Respiratoires de l’Isère, and Comité Scientifique AGIRadom 2011. France (Paris): Ministère de l’Emploi et de la Solidarité, Direction Générale de la Sante, Union Chimique Belge-Pharma, Aventis, Glaxo France, Agence Nationale de la Santé, Région Ile de France, and Domaine d’intérêt majeur. Germany: Bundesminister für Forschung und Technologie. Germany (Erfurt): DFG—German Research Foundation (FR1526/1–1, HE 3294/10–1). Norway (Bergen): Norwegian Research Council (no. 101422/310, no. 214123), Norwegian Asthma and Allergy Association, Glaxo Wellcome AS, Norway Research Fund, Western Norway Regional Health Authorities (no. 911631), and the Bergen Medical Research Foundation. Spain: Ministerio de Sanidad y Consumo FIS (no. 91/0016060/00E-05E, no. 93/0393, no. 97/0035–01, no. 99/0034–01, no. 99/0034–02). Spain (Galdakao): Basque Health Department and FIS (no. 09/01511). Sweden (Gothenburg, Umeå, and Uppsala): the Swedish Medical Research Council, Swedish Heart-Lung Foundation, Swedish Association against Asthma and Allergy, Swedish Cancer and Allergy Foundation, and Swedish Council for Working Life and Social Research. European Commission (no. 018996–GABRIEL); and the Wellcome Trust (WT084703MA). United Kingdom: Asthma UK (formerly known as National Asthma Campaign), Department of Health, South Thames Regional Health Authority, and the Medical Research Council (G0901214/1). The coordination of the European Community Respiratory Health Survey II was supported by the European Commission. The coordination of ECRHS III was supported by the Medical Research Council (G0901214/1). NFBC1966 received financial support related to the present work from the Academy of Finland (project grants 104781, 120315, 129269, 1114194, 24300796, 85547, Center of Excellence in Complex Disease Genetics), University Hospital Oulu, Biocenter, University of Oulu, Finland (75617), NHLBI grant 5R01HL087679–02 through the STAMPEED program (1RL1MH083268–01), NIH/NIMH (5R01MH63706:02), the EU FP5 EURO-BLCS, QLG1-CT-2000-01643, ENGAGE project and grant agreement HEALTH-F4–2007-201413, EU FP7 EurHEALTHAgeing 277849, the Medical Research Council (MRC), UK (G0500539, G0600705, G1002319, PrevMetSyn/SALVE) and ERDF European Regional Development Fund Grant no. 539/2010 A31592. The program is currently being funded by the EU H2020--PHC-2014 DynaHEALTH action (grant agreements No. 633595), EU H2020-HCO-2004 iHEALTH Action, EU H2020-PHC-2014 ALEC Action (grant agreement No. 633212), EU H2020-SC1–2016-2017 LIFECYCLE Action, EU H2020-MSCA-ITN-2016 CAPICE Action, Academy of Finland EGEA-project (285547) and MRC Grant nro MR/M013138/1. In NFBC, DNA extractions, sample quality controls, biobank up-keeping and aliquotting was supported financially by the Academy of Finland and Biocentrum Helsinki.
EU Grant Number: (277849) EURHEALTHAGEING - European ResearcH on DevElopmentAL, BirtH and Genetic Determinants of Ageing
(733206) LIFECYCLE - Early-life stressors and LifeCycle health
(633595) DYNAHEALTH - Understanding the dynamic determinants of glucose homeostasis and social capability to promote Healthy and active aging
(643774) iHealth-T2D - Family-based intervention to improve healthy lifestyle and prevent Type 2 Diabetes amongst South Asians with central obesity and prediabetes
Academy of Finland Grant Number: 129269
Detailed Information: 129269 (Academy of Finland Funding decision)
285547 (Academy of Finland Funding decision)
114194 (Academy of Finland Funding decision)
Copyright information: © The Author(s). 2018. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (, which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( applies to the data made available in this article, unless otherwise stated.