Genome-wide association study of lung function decline in adults with and without asthma

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...

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Published in:Journal of allergy and clinical immunology 2012-05, Vol.129 (5), p.1218-1228
Main Authors: Imboden, Medea, PhD, Bouzigon, Emmanuelle, MD, PhD, Curjuric, Ivan, MD, Ramasamy, Adaikalavan, PhD, Kumar, Ashish, MSc, Hancock, Dana B., PhD, Wilk, Jemma B., DSc, Vonk, Judith M., PhD, Thun, Gian A., MSc, Siroux, Valerie, PhD, Nadif, Rachel, PhD, Monier, Florent, MSc, Gonzalez, Juan R., PhD, Wjst, Matthias, MD, MD, Heinrich, Joachim, PhD, Loehr, Laura R., MD, PhD, Franceschini, Nora, MD, MPH, North, Kari E., PhD, Altmüller, Janine, MD, Koppelman, Gerard H., MD, PhD, Guerra, Stefano, MD, PhD, Kronenberg, Florian, MD, Lathrop, Mark, PhD, Moffatt, Miriam F., DPhil, O’Connor, George T., MD, MSc, Strachan, David P., MD, Postma, Dirkje S., MD, PhD, London, Stephanie J., MD, DrPH, Schindler, Christian, PhD, Kogevinas, Manolis, MD, Kauffmann, Francine, MD, Jarvis, Debbie L., MD, Demenais, Florence, MD, Probst-Hensch, Nicole M., PhD
Format: Article
Language:English
Subjects:
Adult
Age
Air pollution
Allergies
Allergy and Immunology
Arteriosclerosis
Asthma
Asthma - diagnosis
Asthma - epidemiology
Asthma - genetics
Asthma - physiopathology
Biological and medical sciences
Chromosomes, Human, Pair 13
Chromosomes, Human, Pair 13 - genetics
Chronic obstructive pulmonary disease
Chronic obstructive pulmonary disease, asthma
cohort studies
Europe
Female
Follow-Up Studies
Forced Expiratory Volume
Fundamental and applied biological sciences. Psychology
Fundamental immunology
Genealogy
Genetics
genome-wide association
Genome-Wide Association Study
Genomes
Health risk assessment
Heart
Heart diseases
heterogeneity
Humans
Immunopathology
Life Sciences
Lung
Lung - metabolism
Lung - pathology
lung function decline
Male
Medical sciences
Membrane Proteins
Membrane Proteins - genetics
Middle Aged
Neoplasm Proteins
Obstructive lung disease
Pneumology
Pollution effects
Polymorphism, Single Nucleotide
Population
Replication
Respiratory diseases
Respiratory function
Review boards
Santé publique et épidémiologie
Sarcoidosis. Granulomatous diseases of unproved etiology. Connective tissue diseases. Elastic tissue diseases. Vasculitis
Sensitivity analysis
Single-nucleotide polymorphism
Studies
Tumor Suppressor Proteins
Tumor Suppressor Proteins - genetics
Vital Capacity
Young Adult
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Summary: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.
ISSN:0091-6749
1097-6825
DOI:10.1016/j.jaci.2012.01.074