Marie-Hélène Dizier, Rachel Nadif, Orianne Dumas, Amar J. Mehta, Ismaïl Ahmed, Jan-Paul Zock, Pascale Tubert-Bitter, Juan R. González, Medea Imboden, Emmanuelle Bouzigon, Ivan Curjuric, Deborah Jarvis, Florence Demenais, Marta Rava, Nicole Probst-Hensch, Nicole Le Moual, Manolis Kogevinas, Vieillissement et Maladies chroniques : approches épidémiologique et de santé publique (VIMA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Spanish National Cancer Research Center (CNIO), Biostatistique, Biomathématique, Pharmacoépidémiologie et Maladies Infectieuses (B2PHI), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Center for Research in Environmental Epidemiology (CREAL), Universitat Pompeu Fabra [Barcelona] (UPF)-Catalunya ministerio de salud, Variabilité Génétique et Maladies Humaines, Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Epidemiology & Public Health [Basel, Switzerland], Swiss Tropical and Public Health Institute [Basel]-Medical School University of Basel, Department of Environmental Health [Boston, USA], Harvard School of Public Health, Centre for Research in Environmental Epidemiology (CREAL), Universitat Pompeu Fabra [Barcelona] (UPF), Respiratory Epidemiology and Public Health Group [London, U.K.], National Heart and Lung Institute-Imperial College London, U946, Fondation Jean Dausset/CEPH, Institut National de la Santé et de la Recherche Médicale (INSERM), The genotyping of all three studies was funded by the French National Agency of Research (ANR-PRSP 2009: IAGO), and by the European Commission (contract n° 018996) (GABRIEL) and the Wellcome Trust grant (WT 084703MA), both awarded to the GABRIEL consortium (a multidisciplinary study to identify the genetic and environmental causes of asthma in the European Community). EGEA: Research funded by the French Agency of health safety, environment and work (AFSSET, EST-09-15). SAPALDIA: The Swiss National Science Foundation (grants no 33CS30-148470/1, 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.ECRHS: The co-ordination of ECRHS II was supported by the European Commission, as part of their Quality of Life program. This work was also funded by the US National Institutes of Health (NIH grant 1R01HL062633) and the Carlos III Health Institute of the Spanish Ministry of Health and Consumption (FIS grant 01/3058). The following bodies funded the local studies in ECRHS II included in this paper: Albacete: Fondo de Investigaciones Santarias (FIS) (grant code: 97/0035-01, 99/0034-01 and 99/0034-02), Hospital Universitario de Albacete, Consejeria de Sanidad, Barcelona: SEPAR, Public Health Service (grant code: R01 HL62633-01), Fondo de Investigaciones Santarias (FIS) (grant code:97/0035-01, 99/0034-01 and 99/0034-02) CIRIT (grant code: 1999SGR 00241) Red Respira ISCII, Basel: Swiss National Science Foundation, Swiss Federal Office for Education & Science, Swiss National Accident Insurance Fund (SUVA), USC NIEHS Center grant 5P30 ES07048, Bergen: Norwegian Research Council, Norwegian Asthma & Allergy Association (NAAF), Glaxo Wellcome AS, Norway Research Fund, Erfurt: GSF-National Research Centre for Environment & Health, Deutsche Forschungsgemeinschaft (DFG) (grant code FR 1526/1-1), Galdakao: Basque Health Dept, Grenoble: Programme Hospitalier de Recherche Clinique-DRC de Grenoble 2000 no. 2610, Ministry of Health, Direction de la Recherche Clinique, Ministere de l'Emploi et de la Solidarite, Direction Generale de la Sante, CHU de Grenoble, Comite des Maladies Respiratoires de l’Isere, Hamburg: GSF-National Reasearch Centre for Environment & Health, Deutsche Forschungsgemeinschaft (DFG) (grant code MA 711/4-1), Ipswich and Norwich: Asthma UK (formerly known as National Asthma Campaign), Huelva: Fondo de Investigaciones Santarias (FIS) (grant code: 97/0035-01, 99/0034-01 and 99/0034-02), Oviedo: Fondo de Investigaciones Santarias (FIS) (grant code: 97/0035-01, 99/0034-01 and 99/0034-02), Paris: Ministere de l'Emploi et de la Solidarite, Direction Generale de la Sante, UCB-Pharma (France), Aventis (France), Glaxo France, Programme Hospitalier de Recherche Clinique-DRC de Grenoble 2000 no. 2610, Ministry of Health, Direction de la Recherche Clinique, CHU de Grenoble, Tartu: Estonian Science Foundation, Umeå: Swedish Heart Lung Foundation, Swedish Foundation for Health Care Sciences & Allergy Research, Swedish Asthma & Allergy Foundation, Swedish Cancer & Allergy Foundation, Uppsala: Swedish Heart Lung Foundation, Swedish Foundation for Health Care Sciences & Allergy Research, Swedish Asthma & Allergy Foundation, Swedish Cancer & Allergy Foundation., French National Agency of Research (Francia), Unión Europea. Comisión Europea, Wellcome Trust, Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Imperial College London-National Heart and Lung Institute
BACKGROUND: The biological mechanisms by which cleaning products and disinfectants-an emerging risk factor-affect respiratory health remain incompletely evaluated. Studying genes by environment interactions (G × E) may help identify new genes related to adult-onset asthma. OBJECTIVES: We identified interactions between genetic polymorphisms of a large set of genes involved in the response to oxidative stress and occupational exposures to low molecular weight (LMW) agents or irritants on adult-onset asthma. METHODS: Our data came from three large European cohorts: Epidemiological Family-based Study of the Genetics and Environment of Asthma (EGEA), Swiss Cohort Study on Air Pollution and Lung and Heart Disease in Adults (SAPALDIA), and European Community Respiratory Health Survey in Adults (ECRHS). A candidate pathway-based strategy identified 163 genes involved in the response to oxidative stress and potentially related to exposures to LMW agents/irritants. Occupational exposures were evaluated using an asthma job-exposure matrix and job-specific questionnaires for cleaners and healthcare workers. Logistic regression models were used to detect G × E interactions, adjusted for age, sex, and population ancestry, in 2,599 adults (mean age, 47 years; 60% women, 36% exposed, 18% asthmatics). p-Values were corrected for multiple comparisons. RESULTS: Ever exposure to LMW agents/irritants was associated with current adult-onset asthma [OR = 1.28 (95% CI: 1.04, 1.58)]. Eight single nucleotide polymorphism (SNP) by exposure interactions at five loci were found at p < 0.005: PLA2G4A (rs932476, chromosome 1), near PLA2R1 (rs2667026, chromosome 2), near RELA (rs931127, rs7949980, chromosome 11), PRKD1 (rs1958980, rs11847351, rs1958987, chromosome 14), and PRKCA (rs6504453, chromosome 17). Results were consistent across the three studies and after accounting for smoking. CONCLUSIONS: Using a pathway-based selection process, we identified novel genes potentially involved in adult asthma by interaction with occupational exposure. These genes play a role in the NF-κB pathway, which is involved in inflammation. Citation: Rava M, Ahmed I, Kogevinas M, Le Moual N, Bouzigon E, Curjuric I, Dizier MH, Dumas O, Gonzalez JR, Imboden M, Mehta AJ, Tubert-Bitter P, Zock JP, Jarvis D, Probst-Hensch NM, Demenais F, Nadif R. 2017. Genes interacting with occupational exposures to low molecular weight agents and irritants on adult-onset asthma in three European studies. Environ Health Perspect 125:207-214; http://dx.doi.org/10.1289/EHP376. We thank all study members and staff involved in data collections in each cohort: EGEA: We thank the Epidemiological Study on Genetics and Environment of Asthma (EGEA) cooperative group members as follows. Coordination: V. Siroux [epidemiology, principal investigator (PI) since 2013]; F. Demenais (genetics); I. Pin (clinical aspects); R. Nadif (biology); F. Kauffmann (PI 1992–2012). Respiratory epidemiology: Inserm U 700, Paris: M. Korobaeff (EGEA1), F. Neukirch (EGEA1); Inserm U 707, Paris: I. Annesi-Maesano (EGEA1–2); Inserm U1168 (ex-CESP/U 1018), Villejuif: F. Kauffmann, N. Le Moual, R. Nadif, M.P. Oryszczyn (EGEA1–2), R. Varraso; Inserm U 823, Grenoble: V. Siroux. Genetics: Inserm U 393, Paris: J. Feingold; Inserm U 946, Paris: E. Bouzigon, F. Demenais, M.H. Dizier; CNG, Evry: I. Gut (now CNAG, Barcelona, Spain), M. Lathrop (now McGill University, Montreal, Canada). Clinical centers: Grenoble: I. Pin, C. Pison; Lyon: D. Ecochard (EGEA1), F. Gormand, Y. Pacheco; Marseille: D. Charpin (EGEA1), D. Vervloet (EGEA1–2); Montpellier: J. Bousquet; Paris Cochin: A. Lockhart (EGEA1), R. Matran (now in Lille); Paris Necker: E. Paty (EGEA1–2), P. Scheinmann (EGEA1–2); Paris Trousseau: A. Grimfeld (EGEA1–2), J. Just. Data and quality management: Inserm ex-U155 (EGEA1): J. Hochez; Inserm U1168 (ex-CESP/U 1018), Villejuif: N. Le Moual; Inserm ex-U780: C. Ravault (EGEA1–2); Inserm ex-U794: N. Chateigner (EGEA1–2); Grenoble: J. Quentin-Ferran (EGEA1–2). SAPALDIA: We thank the team of the Swiss study on Air Pollution and Lung and Heart Diseases in Adults (SAPALDIA). Study directorate: N.M. Probst-Hensch (PI; e/g); T. Rochat (p), C. Schindler (s), N. Künzli (e/exp), J.M. Gaspoz (c). Scientific team: J.C. Barthélémy (c), W. Berger (g), R. Bettschart (p), A. Bircher (a), C. Brombach (n), P.O. Bridevaux (p), L. Burdet (p), D. Felber Dietrich (e), M. Frey (p), U. Frey (pd), M.W. Gerbase (p), D. Gold (e), E. de Groot (c), W. Karrer (p), F. Kronenberg (g), B. Martin (pa), A. Mehta (e), D. Miedinger (o), M. Pons (p), F. Roche (c), T. Rothe (p), P. Schmid- Grendelmeyer (a), D. Stolz (p), A. Schmidt-Trucksäss (pa), J. Schwartz (e), A. Turk (p), A. von Eckardstein (cc), E. Zemp Stutz (e). Scientific team at coordinating centers: M. Adam (e), I. Aguilera (exp), S. Brunner (s), D. Carballo (c), S. Caviezel (pa), I. Curjuric (e), A. Di Pascale (s), J. Dratva (e), R. Ducret (s), E. Dupuis Lozeron (s), M. Eeftens (exp), I. Eze (e), E. Fischer (g), M. Foraster (e), M. Germond (s), L. Grize (s), S. Hansen (e), A. Hensel (s), M. Imboden (g), A. Ineichen (exp), A. Jeong (g), D. Keidel (s), A. Kumar (g), N. Maire (s), A. Mehta (e), R. Meier (exp), E. Schaffner (s), T. Schikowski (e), M. Tsai (exp). Abbreviations: (a) allergology, (c) cardiology, (cc) clinical chemistry, (e) epide - miology, (exp) exposure, (g) genetic and molecular biology, (m) meteorology, (n) nutrition, (o) occupational health, (p) pneumology, (pa) physical activity, (pd) pediatrics, (s) statistics. The study could not have been done without the help of the study partici - pants, technical and administrative support and the medical teams and field workers at the local study sites. Local fieldworkers: Aarau: S. Brun, G. Giger, M. Sperisen, M. Stahel; Basel: C. Bürli, C. Dahler, N. Oertli, I. Harreh, F. Karrer, G. Novicic, N. Wyttenbacher; Davos: A. Saner, P. Senn, R. Winzeler; Geneva: F. Bonfils, B. Blicharz, C. Landolt, J. Rochat; Lugano: S. Boccia, E. Gehrig, M.T. Mandia, G. Solari, B. Viscardi; Montana: A.P. Bieri, C. Darioly, M. Maire; Payerne: F. Ding, P. Danieli, A. Vonnez; Wald: D. Bodmer, E. Hochs, R. Kunz, C. Meier, J. Rakic, U. Schafroth, A. Walder. Administrative staff: N. Bauer Ott, C. Gabriel, R. Gutknecht. ECRHS: The ECRHS data incorporated in this analysis would not have been available without the collaboration of the following individuals and their research teams. ECRHS Co-ordinating Centre. P. Burney, D. Jarvis, S. Chinn, J. Knox (ECRHS II), C. Luczynska†, J. Potts. Steering Committee for ECRHS II. P. Burney, D. Jarvis, S. Chinn, U. Ackermann-Liebrich, J.M. Anto, I. Cerveri, R. deMarco†, T. Gislason, J. Heinrich, C. Janson, N. Kunzli, B. Leynaert, F. Neukirch, J. Schouten, J. Sunyer; C. Svanes, P. Vermeire†, M. Wjst. Principal Investigators and Senior Scientific Teams for ECRHS II centers within this analysis: Estonia: Tartu (R. Jogi, A. Soon); France: Paris (F. Neukirch, B. Leynaert, R. Liard, M. Zureik), Grenoble (I. Pin, J. Ferran-Quentin); Germany: Erfurt (J. Heinrich, M. Wjst, C. Frye, I. Meyer), Hamburg (K. Richter, D. Nowak); Norway: Bergen (A. Gulsvik, E. Omenaas, C. Svanes, B. Laerum); Spain: Barcelona (J.M. Anto, J. Sunyer, M. Kogevinas, J.P. Zock, X. Basagana, A. Jaen, F. Burgos), Huelva (J. Maldonado, A. Pereira, J.L. Sanchez), Albacete (J. Martinez-Moratalla Rovira, E. Almar), Galdakao (N. Muniozguren, I. Urritia), Oviedo (F. Payo); Sweden: Uppsala (C. Janson, G. Boman, D. Norback, M. Gunnbjornsdottir), Umeå (E. Norrman, M. Soderberg, K. Franklin, B. Lundback, B. Forsberg, L. Nystrom); Switzerland: Basel (N. Kunzli, B. Dibbert, M. Hazenkamp, M. Brutsche, U. Ackermann-Liebrich); United Kingdom: Norwich (D. Jarvis, B. Harrison), Ipswich (D. Jarvis, R. Hall, D. Seaton). Sí