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Identification of a new locus at 16q12 associated with time-to-asthma onset

Chloé Sarnowski 1, 2, 3 Pierre-Emmanuel Sugier 2, 3, 1 Raquel Granell 4 Debbie Jarvis 5, 6 Marie-Hélène Dizier 2, 3, 1 Markus Ege 7, 8 Medea Imboden 9, 10 Catherine Laprise 11 Elza Khusnutdinova 12, 13 Maxim Freidin 14 William Cookson 15 Miriam Moffatt 15 Mark Lathrop 16 Valérie Siroux 17 Ludmila Ogorodova 18 Alexandra Karunas 12, 13 Alan James 19, 20 Nicole Probst-Hensch 9, 10 Erika Von Mutius 7, 8 Isabelle Pin 17 Manolis Kogevinas 21, 22 John Henderson 4 Florence Demenais 2, 3, 1 Emmanuelle Bouzigon 2, 3, 1, *
* Corresponding author
1 USPC - Université Sorbonne Paris Cité
2 Variabilité Génétique et Maladies Humaines
3 IUH - Institut Universitaire d'Hématologie
4 School of Social and Community Medicine [Bristol]
5 Respiratory Epidemiology, Occupational Medicine & Public Health [London]
6 MRC-­PHE Centre for Environment & Health
7 Dr von Hauner Children's Hospital [Munich, Germany]
8 CPC -M - Comprehensive Pneumology Center Munich [Munich, Germany]
9 Swiss Tropical and Public Health Institute [Basel]
10 Unibas - University of Basel
11 Département des Sciences Fondamentales [Saguenay, QC, Canada]
12 Institute of Biochemistry and Genetics [Bashkortostan Republic, Russia]
13 Department of Genetics and Fundamental Medicine [Bashkortostan Republic, Russia]
14 Population Genetics Laboratory [Tomsk, Russia]
15 National Heart and Lung Institute [London, UK]
16 Genome Quebec Innovation Centre [Montréal, Canada]
17 CRI INSERM/UJF - U823 - Equipe d'Épidémiologie Environnementale appliquée à la Reproduction et la Santé Respiratoire
INSERM U823 - Institut d'oncologie/développement Albert Bonniot de Grenoble
18 Central Research Laboratory [Tomsk, Russia]
19 School of Population Health [Crawley, Western Australia]
20 Department of Pulmonary Physiology and Sleep Medicine [Nedlands, Western Australia]
21 CIBER de Epidemiología y Salud Pública (CIBERESP)
22 CREAL - Centre for Research in Environmental Epidemiology [Barcelona, Spain]
Abstract : Background: Asthma is a heterogeneous disease in which age-of-onset plays an important role. Objective: We sought to identify the genetic variants associated with time-to-asthma onset. Methods: We conducted a large-scale meta-analysis of nine genome-wide association studies of time-to-asthma onset (total of 5,462 asthmatics with a broad range of age-of-asthma onset and 8,424 controls of European ancestry) performed using survival analysis techniques. Results: We detected five regions associated with time-to-asthma onset at genome-wide significant level (P<5x10-8). We evidenced a new locus in 16q12 region (near cylindromatosis turban tumor syndrome gene (CYLD)) and confirmed four asthma risk regions: 2q12 (IL1RL1), 6p21 (HLA-DQA1), 9p24 (IL33) and 17q12-q21 (ZPBP2-GSDMA). Conditional analyses identified two distinct signals at 9p24 (both upstream of IL33) and at 17q12-q21 (near ZPBP2 and within GSDMA). These seven distinct loci explained together 6.0% of the variance in time-to-asthma onset. In addition, we showed that genetic variants at 9p24 and 17q12-q21 were strongly associated with an earlier onset of childhood asthma (P≤0.002) whereas 16q12 SNP was associated with a later asthma onset (P=0.04). A high burden of disease risk alleles at these loci was associated with earlier age-of-asthma onset (4 years versus 9-12 years, P=10-4). Conclusion: The new susceptibility region for time-to-asthma onset at 16q12 harbors variants that correlate with the expression of CYLD and NOD2 (nucleotide-binding oligomerization domain 2), two strong candidates for asthma. This study demonstrates that incorporating the variability of age-of-asthma onset in asthma modeling is a helpful approach in the search for disease susceptibility genes.
Keywords : CYLD Asthma NOD2 survival analysis genome-wide association study age of onset conditional analysis genetics
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https://www.hal.inserm.fr/inserm-01321840
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Submitted on : Thursday, May 26, 2016 - 12:36:06 PM
Last modification on : Monday, November 16, 2020 - 3:26:09 PM
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Chloé Sarnowski, Pierre-Emmanuel Sugier, Raquel Granell, Debbie Jarvis, Marie-Hélène Dizier, et al.. Identification of a new locus at 16q12 associated with time-to-asthma onset. Journal of Allergy and Clinical Immunology, Elsevier, 2016, 138 (4), pp.1071-1080. ⟨10.1016/j.jaci.2016.03.018⟩. ⟨inserm-01321840⟩

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