TY - JOUR
T1 - SERPINA1 methylation and lung function in tobacco-smoke exposed European children and adults
T2 - a meta-analysis of ALEC population-based cohorts.
AU - Beckmeyer-Borowko, Anna
AU - Imboden, Medea
AU - Rezwan, Faisal
AU - Wielscher, Matthias
AU - Amaral, Andre F. S.
AU - Jeong, Ayoung
AU - Schaffner, Emmanuel
AU - Auvinen, Juha
AU - Sebert, Sylvian
AU - Karhunen, Villa
AU - Bettschart, Robert
AU - Turk, Alexander
AU - Pons, Marco
AU - Stolz, Daiana
AU - Kronenberg, Florian
AU - Arathimos, Ryan
AU - Sharp, Gemma C.
AU - Relton, Caroline
AU - Henderson, Alexander J.
AU - Jarvelin, Marjo-Rittaa
AU - Jarvis, Deborah
AU - Holloway, John W.
AU - Probst-Hensch, Nicole
N1 - Funding Information:
The following authors report no competing interests: ABB, MI, FR, MW, AFSA, AJ, ES, JA, SS, VK, RB, AT, MP, FK, RA, GCS, CR, MRJ, NMPH. DS reports consultancy at Roche AG, Novartis AG, Astra-Zeneca AG, GSK AG; grants and pending grants at Astra-Zeneca AG, Pan Gas AG, Weimann AG, Curetis AG, Swiss National foundation (PP00-P3–128412/1), Astra Zeneca AG and payments for lectures including speakers bureaus at Novartis AG. AJH reports grants from Medical Research Council and grants from Wellcome during the conduct of the study. DJ and JWH report grants from European Union during the conduct of the study.
Funding Information:
The ALEC Study is funded by the European Union’s Horizon 2020 Research and Innovation programme under grant agreement No. 633212. The ALEC study leader is Deborah Jarvis. The manuscript was done under ALEC Work-package 5 led by Nicole Probst-Hensch. Other Work-package leaders in ALEC are Cecilie Svanes, John Henderson, Judith Garcia-Aymerich, and Cosetta Minelli. The ALEC International Scientific Advisory Board is: Marike Boezen (University Medical Center Groningen, University of Groningen, Groningen, The Netherlands); Bernice Elger (Institute for Biomedical Ethics, University of Basel, Basel, Switzerland); Bo Alexander Gleditsch (The Norwegian Asthma and Allergy Association, Norway); Bas Heijmans (Department of Medical Statistics and Bioinformatics, Leiden University Medical Center, Leiden, The Netherlands); Isabelle Romieu (National Institute of Public Health, Cuernavaca, Mexico; and Emory University, Atlanta, US); John Thompson (Department of Health Sciences, University of Leicester, Leicester, UK). 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. The ALSPAC work was supported by the MRC Integrative Epidemiology Unit, The UK Medical Research Council and Wellcome (Grant ref.: 102215/2/13/2) and the University of Bristol (MC_UU_12013_2, MC_UU_12013_5 and MC_UU_12013_8). The Accessible Resource for Integrated Epigenomics Studies (ARIES) which generated large scale methylation data was funded by the UK Biotechnology and Biological Sciences Research Council (BB/I025751/1 and BB/I025263/1). Additional epigenetic profiling on the ALSPAC cohort was supported by the UK Medical Research Council Integrative Epidemiology Unit and the University of Bristol (MC_UU_12013_1, MC_UU_12013_2, MC_UU_12013_5 and MC_UU_12013_8), the Wellcome Trust (WT088806) and the United States National Institute of Diabetes and Digestive and Kidney Diseases (R01 DK10324).
Funding Information:
We thank the High-Throughput Genomics Group at the Wellcome Trust Centre for Human Genetics (funded by Wellcome Trust grant reference 090532/Z/09/Z) for the generation of Methylation data in SAPALDIA and the National Public Health Institute, Biomedicum Helsinki in Finland to have performed DNA extractions, sample quality controls, biobank up-keeping and aliquotting in NFBC. We would like to acknowledge the scientific teams, the field workers and the administrative staff of the SAPALDIA, ECRHS, NFBC, and ALSPAC teams. We are most grateful to all study participants and their families for having donated time, data, and biospecimens to these studies. We thank the late Professor Paula Rantakallio for the launch of NFBC1966.
Publisher Copyright:
© 2018 The Author(s).
PY - 2018/8/22
Y1 - 2018/8/22
N2 - 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.
AB - 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.
KW - Alpha-1 antitrypsin
KW - Chronic obstructive pulmonary disease; SERPINA1 methylation
KW - DNA methylation
KW - Epigenetics
KW - Population based study
KW - Smoking
KW - Humans
KW - Middle Aged
KW - Child, Preschool
KW - Infant
KW - Male
KW - alpha 1-Antitrypsin/genetics
KW - Tobacco Smoke Pollution/adverse effects
KW - Young Adult
KW - Europe/epidemiology
KW - Adult
KW - DNA Methylation/physiology
KW - Female
KW - Lung/drug effects
KW - Child
KW - Infant, Newborn
KW - Cross-Sectional Studies
KW - Population Surveillance/methods
KW - Tobacco/adverse effects
KW - Adolescent
KW - Aged
KW - Longitudinal Studies
KW - Cohort Studies
KW - Nicotiana/adverse effects
UR - http://europepmc.org/abstract/med/30134983
UR - http://www.scopus.com/inward/record.url?scp=85052160202&partnerID=8YFLogxK
U2 - 10.1186/s12931-018-0850-8
DO - 10.1186/s12931-018-0850-8
M3 - Article
C2 - 30134983
SN - 1465-9921
VL - 19
JO - Respiratory Research
JF - Respiratory Research
IS - 1
M1 - 156
ER -