期刊
JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY
卷 138, 期 4, 页码 1071-1080出版社
MOSBY-ELSEVIER
DOI: 10.1016/j.jaci.2016.03.018
关键词
Asthma; age of onset; genetics; genome-wide association study; survival analysis; conditional analysis; CYLD; NOD2
资金
- French National Agency for Research [ANR-CES-2009, ANR-11-BSV1-027-GWIS-AM]
- Region Ile-de-France (DIM-SEnT grant)
- Fonds de dotation Recherche en Sante Respiratoire
- Russian Foundation for Basic Research [13-04-01397, 01-04-48213a]
- Healthway
- UK Medical Research Council
- Wellcome Trust [102215/2/13/2, WT084703MA]
- University of Bristol
- Swiss National Science Foundation [33CS30-148470/1]
- Canadian Institutes of Health Research (CIHR)
- European Commission [LSHB-CT-2006-018996-GABRIEL]
- Departments of Science and Health of the Government of Western Australia
- MRC [G0401540] Funding Source: UKRI
- Medical Research Council [MC_PC_15018, G9815508, G0401540] Funding Source: researchfish
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 (TAO). Methods: 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. Results: We detected 5 regions associated with TAO at the genome-wide significant level (P < 5 x 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)). Conclusion: 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.
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