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

Medea Imboden 1 Emmanuelle Bouzigon 2, 3 Ivan Curjuric 1 Adaikalavan Ramasamy 4 Ashish Kumar 1, 5 Dana B. Hancock 6, 7 Jemma B. Wilk 8 Judith M. Vonk 9 Gian A. Thun 1 Valerie Siroux 10 Rachel Nadif 11 Florent Monier 2, 3 Juan R. Gonzalez 12, 13 Matthias Wjst 14 Joachim Heinrich 14 Laura R. Loehr 15 Nora Franceschini 15 Kari E. North 15 Janine Altmüller 16 Gerard H. Koppelman 9 Stefano Guerra 12, 13, 17 Florian Kronenberg 18 Mark Lathrop 2, 19, 20 Miriam F. Moffatt 21 George T. O'Connor 8, 22 David P. Strachan 23 Dirkje S. Postma 9 Stephanie J. London 6 Christian Schindler 1 Manolis Kogevinas 12, 13, 24 Francine Kauffmann 11 Debbie L. Jarvis 4 Florence Demenais 2, 3 Nicole M. Probst-Hensch 1, * 
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 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.
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Submitted on : Tuesday, October 23, 2012 - 5:28:11 PM
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Medea Imboden, Emmanuelle Bouzigon, Ivan Curjuric, Adaikalavan Ramasamy, Ashish Kumar, et al.. Genome-wide association study of lung function decline in adults with and without asthma.. Journal of Allergy and Clinical Immunology, Elsevier, 2012, 129 (5), pp.1218-28. ⟨10.1016/j.jaci.2012.01.074⟩. ⟨inserm-00744741⟩



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