Details

Autor(en) / Beteiligte

• Sarnowski, Chloé, PhD
• Sugier, Pierre-Emmanuel, MSc
• Granell, Raquel, PhD
• Jarvis, Debbie, MD
• Dizier, Marie-Hélène, PhD
• Ege, Markus, MD
• Imboden, Medea, PhD
• Laprise, Catherine, PhD
• Khusnutdinova, Elza K., PhD
• Freidin, Maxim B., PhD
• Cookson, William O.C., MD, DPhil
• Moffatt, Miriam, DPhil
• Lathrop, Mark, PhD
• Siroux, Valérie, PhD
• Ogorodova, Ludmila M., MD, PhD
• Karunas, Alexandra S., MD, PhD
• James, Alan, MD
• Probst-Hensch, Nicole M., PhD
• von Mutius, Erika, MD
• Pin, Isabelle, MD, PhD
• Kogevinas, Manolis, MD, PhD
• Henderson, A. John, MD
• Demenais, Florence, MD
• Bouzigon, Emmanuelle, MD, PhD

Titel

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

Ist Teil von

• Journal of allergy and clinical immunology, 2016-10, Vol.138 (4), p.1071-1080

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2016

Quelle

Free E-Journal (出版社公開部分のみ）

Beschreibungen/Notizen

• 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 × 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.