Genome-wide association study of lung function decline in adults with and without asthma - 28/04/12

Doi : 10.1016/j.jaci.2012.01.074

Medea Imboden, PhD ^a,^b,^{^{These authors contributed equally to this work.}}, Emmanuelle Bouzigon, MD, PhD ^c,^d,^e,^{^{These authors contributed equally to this work.}}, Ivan Curjuric, MD ^a,^b, Adaikalavan Ramasamy, PhD ^f, Ashish Kumar, MSc ^a,^b,^g, Dana B. Hancock, PhD ^h,ⁱ, Jemma B. Wilk, DSc ^j, Judith M. Vonk, PhD ^k, Gian A. Thun, MSc ^a,^b, Valerie Siroux, PhD ^l,^m, Rachel Nadif, PhD ^n,^o, Florent Monier, MSc ^c,^d,^e, Juan R. Gonzalez, PhD ^p,^q, Matthias Wjst, MD, MD ^r, Joachim Heinrich, PhD ^r, Laura R. Loehr, MD, PhD ^s, Nora Franceschini, MD, MPH ^s, Kari E. North, PhD ^t, Janine Altmüller, MD ^u, Gerard H. Koppelman, MD, PhD ^k, Stefano Guerra, MD, PhD ^p,^q,^v,^cc, Florian Kronenberg, MD ^w, Mark Lathrop, PhD ^d,^x, Miriam F. Moffatt, DPhil ^y, George T. O’Connor, MD, MSc ^z,^aa, David P. Strachan, MD ^bb, Dirkje S. Postma, MD, PhD ^k, Stephanie J. London, MD, DrPH ^h, Christian Schindler, PhD ^a,^b, Manolis Kogevinas, MD ^p,^q,^cc,^dd, Francine Kauffmann, MD ^n,^o, Debbie L. Jarvis, MD ^f, Florence Demenais, MD ^c,^d,^e, Nicole M. Probst-Hensch, PhD ^a,^b,^⁎
^a Swiss Tropical and Public Health Institute, Basel, Switzerland
^b University of Basel, Basel, Switzerland
^c Inserm, UMRS-946, Paris, France
^d Fondation Jean Dausset–Centre d’Etude du Polymorphisme Humain (CEPH), Paris, France
^e Université Paris Diderot, Paris 7, Institut Universitaire d’Hématologie, Paris, France
^f Respiratory Epidemiology and Public Health, Imperial College, and MRC-HPA Centre for Environment and Health, London, United Kingdom
^g Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom
^h Epidemiology Branch, Division of Intramural Research, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, NC
ⁱ Behavioral Health Epidemiology Program, Research Triangle Institute International, Research Triangle Park, NC
^j Departments of Neurology and Medicine, Boston University School of Medicine, Boston, Mass
^k Department of Pulmonology, Pediatric Pulmonology and Pediatric Allergology, Epidemiology, Beatrix Children’s Hospital, Groningen Research Institute for Asthma and COPD, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
^l Team of Environmental Epidemiology applied to Reproduction and Respiratory Health, Inserm, U823, Grenoble, France
^m Université Joseph Fourier, Grenoble, France
ⁿ Inserm, U1018, CESP Centre for Research in Epidemiology and Population Health, Respiratory and Environmental Epidemiology Team, Villejuif, France
^o Université Paris Sud, UMRS 1018, Villejuif, France
^p Centre for Research in Environmental Epidemiology, Barcelona, Spain
^q CIBER Epidemiologia y Salúd Publica, Barcelona, Spain
^r Institute of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
^s Department of Epidemiology, UNC Gillings School of Global Public Health, University of North Carolina–Chapel Hill, Chapel Hill, NC
^t Department of Epidemiology and Carolina Center for Genome Sciences, University of North Carolina–Chapel Hill, Chapel Hill, NC
^u Cologne Center for Genomics (CCG), University of Cologne, Cologne, Germany
^v Arizona Respiratory Center, University of Arizona, Tucson, Ariz
^w Department of Medical Genetics, Molecular and Clinical Pharmacology, Division of Genetic Epidemiology, Innsbruck Medical University, Innsbruck, Austria
^x Commissariat à l’Energie Atomique, Institut de Génomique, Centre National de Génotypage, Evry, France
^y National Heart and Lung Institute, Imperial College, London, United Kingdom
^z Pulmonary Center, Department of Medicine, Boston University School of Medicine, Boston, Mass
^aa National Heart, Lung, and Blood Institute’s Framingham Heart Study, Framingham, Mass
^bb Division of Population Health Sciences and Education, St George’s, University of London, London, United Kingdom
^cc IMIM (Municipal Institute of Medical Research), Barcelona, Spain
^dd National School of Public Health, Athens, Greece

Corresponding author: Nicole M. Probst-Hensch, PhD, SwissTPH, Socinstr. 57, 4002 Basel, Switzerland.

Abstract

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 FEV₁ 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 FEV₁ and FEV₁/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 FEV₁ 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 FEV₁/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.

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Key words : Asthma, cohort studies, genome-wide association, lung function decline, heterogeneity

Abbreviations used : ARIC, B58C, COPD, ECRHS, EGEA, FHS, FVC, GWAS, SAPALDIA, SNP

Plan

Methods

Discovery cohorts and study population

Lung function assessments, asthma status, and genotypes

Replication cohorts

Statistical analysis

Results

Characteristics of the study populations

Main findings from meta-analyses of discovery and replication phases

Association signals for annual decrease in FEV₁ in nonasthmatic participants

Association signals for annual decrease in FEV₁ in asthmatic participants

Association signals for annual decrease in FEV₁/FVC ratio in nonasthmatic participants

Association signals for annual decrease in FEV₁/FVC ratio in asthmatic participants

SNPs previously associated in GWAS meta-analyses on cross-sectional lung function

Summary of findings from sensitivity analyses

Discussion

Information on support for this research is provided in the acknowledgments section of this article.

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.

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Vol 129 - N° 5

P. 1218-1228 - mai 2012 Retour au numéro

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Genome-wide association study of lung function decline in adults with and without asthma - 28/04/12

Abstract

Background

Objective

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Results

Conclusions

Plan

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