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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, *
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.
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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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