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

Sarnowski, C.; Sugier, P.E.; Granell, R.; Jarvis, D.; Dizier, M.H.; Ege, M.; Imboden, M.; Laprise, C.; Khusnutdinova, E.K.; Freidin, M.B.; Cookson, W.O.; Moffatt, M.; Lathrop, M.; Siroux, V.; Ogorodova, L.M.; Karunas, A.S.; James, A.; Probst-Hensch, N.M.; von Mutius, E.; Pin, I.; Kogevinas, M.; Henderson, A.J.; Demenais, F.; Bouzigon, E.

Авторы: Sarnowski C., Sugier P.E., Granell R., Jarvis D., Dizier M.H., Ege M., Imboden M., Laprise C., Khusnutdinova E.K., Freidin M.B., Cookson W.O.C, Moffatt M., Lathrop M., Siroux V., Ogorodova L.M., Karunas A.S., James A., Probst-Hensch N.M., von Mutius E., Pin I., Kogevinas M., Henderson A.J., Demenais F., Bouzigon E.
Журнал: Journal of Allergy and Clinical Immunology
Том: 138
Номер: 4
Год издания: 2016
Издательство: Mosby Inc.
Местоположение издательства: United States
Первая страница: 1071
Последняя страница: 1080
DOI: 10.1016/j.jaci.2016.03.018
Аннотация: AbstractBackground: 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.Keywords: Asthma; CYLD; NOD2; age of onset; conditional analysis; genetics; genome-wide association study; survival analysis.
Добавил в систему: Карунас Александра Станиславовна

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

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