Background: Genome-wide association studies have identified determinants of chronic obstructive pulmonary disease, asthma, and lung function level; however, none have addressed decline in lung function. Objective: We conducted the first genome-wide association study on the age-related decrease in FEV 1 and its ratio to forced vital capacity (FVC) stratified a priori by asthma status. Methods: Discovery cohorts included adults of European ancestry (1,441 asthmatic and 2,677 nonasthmatic participants: the Epidemiological Study on the Genetics and Environment of Asthma, the Swiss Cohort Study on Air Pollution and Lung and Heart Disease in Adults, and the European Community Respiratory Health Survey). The associations of FEV 1 and FEV 1/FVC ratio decrease with 2.5 million single nucleotide polymorphisms (SNPs) were estimated. Thirty loci were followed up by in silico replication (1,160 asthmatic and 10,858 nonasthmatic participants: Atherosclerosis Risk in Communities, the Framingham Heart Study, the British 1958 Birth Cohort, and the Dutch Asthma Study). Results: Main signals identified differed between asthmatic and nonasthmatic participants. None of the SNPs reached genome-wide significance. The association between the height-related gene DLEU7 and FEV 1 decrease suggested for nonasthmatic participants in the discovery phase was replicated (discovery, P = 4.8 × 10 -6; replication, P =.03), and additional sensitivity analyses point to a relation to growth. The top ranking signal, TUSC3, which is associated with FEV 1/FVC ratio decrease in asthmatic participants (P = 5.3 × 10 -8), did not replicate. SNPs previously associated with cross-sectional lung function were not prominently associated with decline. Conclusions: Genetic heterogeneity of lung function might be extensive. Our results suggest that genetic determinants of longitudinal and cross-sectional lung function differ and vary by asthma status.
Bibliographical noteFunding Information:
FHS : National Heart, Lung and Blood Institute’s FHS (Contract No. N01-HC-25195) and its contract with Affymetrix, Inc for genotyping services (Contract No. N02-HL-6-4278). Dr. Wilk by a Young Clinical Scientist Award from the Flight Attendant Medical Research Institute (FAMRI). A portion of this research utilized the Linux Cluster for Genetic Analysis (LinGA-II) funded by the Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine and Boston Medical Center .
Dutch Asthma Study : The Dutch Asthma study has been funded by the Netherlands Asthma Foundation grants AF 3.2.07.015 ; and AF 98.48 and a grant from the University Medical Center Groningen .
ECRHS : The coordination of ECRHS II was supported by the European Commission , as part of their Quality of Life programme. The following bodies funded the local studies in ECRHS II: Albacete : Fondo de Investigaciones Santarias (FIS) (grants 97/0035-01, 99/0034-01, and 99/0034-02 ), Hospital Universitario de Albacete, Consejeria de Sanidad; Barcelona : SEPAR, Public Health Service (grant R01 HL62633-01 ), Fondo de Investigaciones Santarias (FIS) (grants 97/0035-01, 99/0034-01, and 99/0034-02 ) CIRIT (grant 1999SGR 00241 ) Red Respira ISCII; CIBER Epidemiologia y Salud Pública (CIBERESP), Spain 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, CHU de Grenoble, Ministere de l’Emploi et de la Solidarite, Direction Generale de la Sante, 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; Financial support for ECRHS I for centers in ECRHS II was provided by: Ministère de la Santé, Glaxo France, Insitut Pneumologique d’Aquitaine, Contrat de Plan Etat-Région Languedoc-Rousillon, CNMATS, CNMRT ( 90MR/10, 91AF/6 ), Ministre delegué de la santé, RNSP, France; GSF , and the Bundesminister für Forschung und Technologie , Bonn, Germany; Norwegian Research Council project no. 101422/310; Ministero Sanidad y Consumo FIS (grants #91/0016060/00E-05E and #93/0393 ), and grants from Hospital General de Albacete, Hospital General Juan Ramón Jiménenz, Consejeria de Sanidad Principado de Asturias, Spain ; The Swedish Medical Research Council, the Swedish Heart Lung Foundation, the Swedish Association against Asthma and Allergy ; Swiss National Science Foundation grant 4026-28099 ; National Asthma Campaign, British Lung Foundation, Department of Health, South Thames Regional Health Authority, UK. A.R. was supported by the Department of Health, UK and the European Commission as part of GABRIEL contract number 018996 under the Integrated Program LSH-2004-1.2.5-1.
Disclosure of potential conflict of interest: J. B. Wilk has received research support from the National Institutes of Health/National Heart, Lung, and Blood Institute and the Flight Attendant Medical Research Institute . G. H. Koppelman has received research support from the Netherlands Asthma Foundation . D. S. Postma is a consultant for Nycomed and has received research support from the Top Institute Pharma and AstraZeneca . F. Kauffmann has received research support from the French Agency of Research, French Agency for Environmental and Occupational Health and Safety, and INSERM−Ministry of Research “Cohortes et Collections.” The rest of the authors declare that they have no relevant conflicts of interest.
SAPALDIA : Swiss National Science Foundation (grants 4026-28099,3347CO-108796, 3247BO-104283, 3247BO-104288, 3247BO-104284, 32-65896.01,32-59302.99, 32-52720.97, 32-4253.94 ); the Federal Office for Forest, Environment, and Landscape; 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, Zurich; the Swiss Lung League; the canton’s Lung League of Basel Stadt/Basel Landschaft, Geneva, Ticino and Zurich; Freie Akademische Gesellschaft (FAG); UBS Wealth Foundation .
EGEA : INSERM–Ministry of Research ‘Cohortes et Collections’ grant ( 4CH06G ), French Ministry of Higher Education and Research, University Paris Diderot-Paris 7, grants from the French Agency for Environmental and Occupational Health Safety (grant AFSSETAPR SE-2004 ), the French National Agency for Research (grants ANR 05-SEST-020-02/05-9-97 and ANR 06-CEBS ), PHRC-Paris, Merck Sharp & Dohme [MSD] ).
B58C : British 1958 Birth Cohort was funded by the Medical Research Council grant G0000934 and the Wellcome Trust grant 068545/Z/02 ( http://www.b58cgene.sgul.ac.uk/ ). Genotyping was funded by the Wellcome Trust grant 076113/B/04/Z , by the United States National Institutes of Health and the Juvenile Diabetes Research Foundation U01 DK062418 and by the European Commission Framework Programme 6 ( 018996 ).
ARIC : The Atherosclerosis Risk in Communities Study is carried out as a collaborative study supported by National Heart, Lung, and Blood Institute contracts ( HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, and HHSN268201100012C), R01HL087641, R01HL59367 and R01HL086694 ; National Human Genome Research Institute contract U01HG004402 ; and National Institutes of Health contract HHSN268200625226C . Infrastructure was partly supported by Grant Number UL1RR025005 , a component of the National Institutes of Health and NIH Roadmap for Medical Research . Work for this manuscript was supported, in part, by the Intramural Research Program of the National Institutes of Health (NIH), National Institute of Environmental Health Sciences (NIEHS, Z01ES043012 ).
Genotyping of the discovery cohort and part of B58C was funded by the GABRIEL asthma genetic consortium supported by a contract from the European Commission ( 018996 ) and grants from the French Ministry of Research , the Wellcome Trust ( WT084703MA ), and Asthma UK .
- cohort studies
- genome-wide association
- lung function decline