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

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• 作者：Chloé ; Sarnowski ; PhD^a ; ^b ; Pierre-Emmanuel Sugier ; MSc^a ; ^b ; Raquel Granell ; PhD^c ; Debbie Jarvis ; MD^d ; ^e ; Marie-Hé ; lè ; ne Dizier ; PhD^a ; ^b ; Markus Ege ; MD^f ; ^g ; Medea Imboden ; PhD^h ; ⁱ ; Catherine Laprise ; PhD^j ; Elza K. Khusnutdinova ; PhD^k ; ^l ; Maxim B. Freidin ; PhD^m ; William O.C. Cookson ; MD ; DPhilⁿ ; Miriam Moffatt ; DPhilⁿ ; Mark Lathrop ; PhD^o ; Valé ; rie Siroux ; PhD^p ; ^q ; ^r ; Ludmila M. Ogorodova ; MD ; PhD^s ; Alexandra S. Karunas ; MD ; PhD^k ; ^l ; Alan James ; MD^t ; Nicole M. Probst-Hensch ; PhD^h ; ⁱ ; Erika von Mutius ; MD^f ; ^g ; Isabelle Pin ; MD ; PhD^p ; ^q ; ^u ; Manolis Kogevinas ; MD ; PhD^v ; ^w ; ^x ; ^y ; A. John Henderson ; MD^c ; Florence Demenais ; MD^a ; ^b ; Emmanuelle Bouzigon ; MD ; PhD^a ; ^b ; ^{emmanuelle.bouzigon@inserm.fr" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Asthma ; age of onset ; genetics ; genome-wide association study ; survival analysis ; conditional analysis ; CYLD ; NOD2
• 刊名：Journal of Allergy and Clinical Immunology
• 出版年：2016
• 出版时间：October 2016
• 年：2016
• 卷：138
• 期：4
• 页码：1071-1080
• 全文大小：1093 K

文摘

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.