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

JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY

卷:138

Article

Sarnowski, Chloe^1,2  Sugier, Pierre-Emmanuel^1,2  Granell, Raquel³  Jarvis, Debbie^4,5  Ege, Markus^6,7  Imboden, Medea^8,9  Laprise, Catherine¹⁰  Khusnutdinova, Elza K.^11,12  Freidin, Maxim B.¹³  Cookson, William O. C.¹⁴  Moffatt, Miriam¹⁴  Lathrop, Mark^15,16  Siroux, Valerie^17,18,19  Ogorodova, Ludmila M.²⁰  Karunas, Alexandra S.^11,12  James, Alan²¹  Probst-Hensch, Nicole M.^8,9  von Mutius, Erika^6,7  Pin, Isabelle^17,18,22  Kogevinas, Manolis^{23,24,25,26,27}  Henderson, A. John³  Demenais, Florence^1,2  Bouzigon, Emmanuelle^1,2 

[1] INSERM, UMR 946, Paris, France

[2] Univ Paris Diderot, Sorbonne Paris Cite, Inst Univ Hematol, Paris, France

[3] Univ Bristol, Sch Social & Community Med, Bristol BS8 1TH, Avon, England

[4] Imperial Coll, Natl Heart & Lung Inst, Resp Epidemiol Occupat Med & Publ Hlth, London, England

[5] MRC PHE Ctr Environm & Hlth, London, England

[6] Univ Munich, Dr Von Hauner Childrens Hosp, Munich, Germany

[7] German Ctr Lung Res, CPC M, Munich, Germany

[8] Swiss Trop & Publ Hlth Inst, Basel, Switzerland

[9] Univ Basel, CH-4003 Basel, Switzerland

[10] Univ Quebec Chicoutimi, Dept Sci Fondamentales, Saguenay, PQ, Canada

[11] Russian Acad Sci, Ufa Sci Ctr, Inst Biochem & Genet, Ufa, Russia

[12] Bashkir State Univ, Dept Genet & Fundamental Med, Ufa, Russia

[13] Res Inst Med Genet, Tomsk, Russia

[14] Imperial Coll London, Natl Heart Lung Inst, London, England

[15] McGill Univ, Montreal, PQ, Canada

[16] Genome Quebec Innovat Ctr, Montreal, PQ, Canada

[17] Univ Grenoble Alpes, IAB, Team Environm Epidemiol Appl Reprod & Resp Hlth, Grenoble, France

[18] INSERM, Grenoble, France

[19] CHU Grenoble, IAB, Team Environm Epidemiol Appl Reprod & Resp Hlth, Grenoble, France

[20] Siberian State Med Univ, Tomsk, Russia

[21] Sir Charles Gairdner Hosp, Dept Pulm Physiol & Sleep Med, Busselton Populat Med Res Inst, Nedlands, WA, Australia

[22] Univ Western Australia, Sch Populat Hlth, Crawley, WA, Australia

[23] CHU Grenoble, Pediat, Grenoble, France

[24] Ctr Res Environm Epidemiol CREAL, Barcelona, Spain

[25] CIBER Epidemiol & Salud Publ CIBERESP, Madrid, Spain

[26] IMIM Hosp Mar Med Res Inst, Barcelona, Spain

[27] Univ Pompeu Fabra, Barcelona, Spain

关键词: Asthma;    age of onset;    genetics;    genome-wide association study;    survival analysis;    conditional analysis;    CYLD;    NOD2;   

DOI  :  10.1016/j.jaci.2016.03.018

来源: Elsevier

【 摘 要 】

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.

【 授权许可】

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