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

Sarnowski, Chloé and Sugier, Pierre-Emmanuel and Granell, Raquel and Jarvis, Debbie and Dizier, Marie-Hélène and Ege, Markus and Imboden, Medea and Laprise, Catherine and Khusnutdinova, Elza K. and Freidin, Maxim B. and Cookson, William O. C. and Moffatt, Miriam and Lathrop, Mark and Siroux, Valérie and Ogorodova, Ludmila M. and Karunas, Alexandra S. and James, Alan and Probst-Hensch, Nicole M. and von Mutius, Erika and Pin, Isabelle and Kogevinas, Manolis and Henderson, A. John and Demenais, Florence and Bouzigon, Emmanuelle. (2016) Identification of a new locus at 16q12 associated with time to asthma onset. Journal of allergy and clinical immunology, 138 (4). pp. 1071-1080.

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Official URL: http://edoc.unibas.ch/44552/

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Abstract

Asthma is a heterogeneous disease in which age of onset plays an important role.; We sought to identify the genetic variants associated with time to asthma onset (TAO).; We conducted a large-scale meta-analysis of 9 genome-wide association studies of TAO (total of 5462 asthmatic patients with a broad range of age of asthma onset and 8424 control subjects of European ancestry) performed by using survival analysis techniques.; We detected 5 regions associated with TAO at the genome-wide significant level (P < 5 × 10(-8)). We evidenced a new locus in the 16q12 region (near cylindromatosis turban tumor syndrome gene [CYLD]) and confirmed 4 asthma risk regions: 2q12 (IL-1 receptor-like 1 [IL1RL1]), 6p21 (HLA-DQA1), 9p24 (IL33), and 17q12-q21 (zona pellucida binding protein 2 [ZPBP2]-gasdermin A [GSDMA]). Conditional analyses identified 2 distinct signals at 9p24 (both upstream of IL33) and 17q12-q21 (near ZPBP2 and within GSDMA). Together, these 7 distinct loci explained 6.0% of the variance in TAO. In addition, we showed that genetic variants at 9p24 and 17q12-q21 were strongly associated with an earlier onset of childhood asthma (P ≤ .002), whereas the 16q12 single nucleotide polymorphism was associated with later asthma onset (P = .04). A high burden of disease risk alleles at these loci was associated with earlier age of asthma onset (4 vs 9-12 years, P = 10(-4)).; The new susceptibility region for TAO at 16q12 harbors variants that correlate with the expression of CYLD and nucleotide-binding oligomerization domain 2 (NOD2), 2 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.
Faculties and Departments:09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH) > Department of Epidemiology and Public Health (EPH) > Chronic Disease Epidemiology > Genetic Epidemiology of Non-Communicable Diseases (Probst-Hensch)
03 Faculty of Medicine > Departement Public Health > Sozial- und Präventivmedizin > Genetic Epidemiology of Non-Communicable Diseases (Probst-Hensch)
09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH)
UniBasel Contributors:Probst Hensch, Nicole and Imboden, Medea
Item Type:Article, refereed
Article Subtype:Research Article
Publisher:Mosby
ISSN:0091-6749
Note:Publication type according to Uni Basel Research Database: Journal article
Identification Number:
Last Modified:03 May 2018 09:40
Deposited On:28 Nov 2016 13:33

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