Genome-wide association study and meta-analysis in multiple populations identifies new loci for peanut allergy and establishes C11orf30/EMSY as a genetic risk factor for food allergy

JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY

卷:141

Article

Asai, Yuka^1,2  Eslami, Aida³  van Ginkel, C. Dorien^4,5  Akhabir, Loubna³  Wan, Ming³  Ellis, George³  Ben-Shoshan, Moshe⁶  Martino, David⁷  Ferreira, Manuel A.⁸  Allen, Katrina⁷  Mazer, Bruce⁶  de Groot, Hans⁹  de Jong, Nicolette W.¹⁰  van Wijk, Roy N. Gerth¹⁰  Dubois, Anthony E. J.⁷  Chin, Rick¹¹  Jorgensen, Eric¹³  Witte, John S.¹²  Melles, Ronald B.¹⁴  Hong, Xiumei¹⁵  Wang, Xiaobin¹⁵  Hui, Jennie¹⁶  Musk, Arthur W. (Bill)¹⁷  Hunter, Michael¹⁸  James, Alan L.^19,20  Koppelman, Gerard H.^4,5  Sandford, Andrew J.³  Clarke, Ann E.¹¹  Daley, Denise³ 

[1] Queens Univ, Div Dermatol, Dept Med, Kingston, ON, Canada

[2] McGill Univ, Div Expt Med, Dept Med, Montreal, PQ, Canada

[3] Univ British Columbia, Ctr Heart Lung Innovat, Vancouver, BC, Canada

[4] Univ Groningen, Univ Med Ctr Groningen, Dept Pediat Pulmonol & Pediat Allergol, Groningen, Netherlands

[5] Univ Groningen, Univ Med Ctr Groningen, GRIAC Res Inst, Groningen, Netherlands

[6] McGill Univ, Montreal Childrens Hosp, Hlth Ctr, Div Allergy & Immunol,Dept Pediat,Res Inst, Montreal, PQ, Canada

[7] Univ Melbourne, Royal Childrens Hosp, Murdoch Childrens Res Inst, Melbourne, Vic, Australia

[8] QIMR Berghofer Med Res Inst, Brisbane, Qld, Australia

[9] Reinier Graaf Gasthuis, Dept Pediat Allergol, Diaconessenhuis Voorburg, Delft, Netherlands

[10] Erasmus MC, Dept Allergol, Rotterdam, Netherlands

[11] Univ Calgary, Cumming Sch Med, Div Rheumatol, Dept Med, Calgary, AB, Canada

[12] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA

[13] Kaiser Permanente Northern Calif, Div Res, Oakland, CA USA

[14] Kaiser Permanente Northern Calif, Redwood City Med Ctr, Dept Ophthalmol, Oakland, CA USA

[15] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Ctr Early Life Origins Dis, Dept Populat Family & Reprod Hlth, Baltimore, MD USA

[16] Univ Western Australia, Australia & Pathol & Lab Med, Sch Populat Hlth, Nedlands, WA, Australia

[17] Univ Western Australia, Sir Charles Gairdner Hosp, Dept Resp Med, Perth, WA, Australia

[18] Univ Western Australia, Sch Populat Hlth, Perth, WA, Australia

[19] Univ Western Australia, Sir Charles Gairdner Hosp, Dept Pulm Physiol & Sleep Med, Perth, WA, Australia

[20] Univ Western Australia, Sch Med & Pharmacol, Perth, WA, Australia

关键词: Peanut allergy;    food allergy;    genome-wide association study;    meta-analysis;    EMSY;    C11orf30;    epigenetics;   

DOI  :  10.1016/j.jaci.2017.09.015

来源: Elsevier

【 摘 要 】

Background: Peanut allergy (PA) is a complex disease with both environmental and genetic risk factors. Previously, PA loci were identified in filaggrin (FLG) and HLA in candidate gene studies, and loci in HLA were identified in a genome-wide association study and meta-analysis. Objective: We sought to investigate genetic susceptibility to PA. Methods: Eight hundred fifty cases and 926 hyper-control subjects and more than 7.8 million genotyped and imputed single nucleotide polymorphisms (SNPs) were analyzed in a genome-wide association study to identify susceptibility variants for PA in the Canadian population. A meta-analysis of 2 phenotypes (PA and food allergy) was conducted by using 7 studies from the Canadian, American (n = 2), Australian, German, and Dutch (n = 2) populations. Results: An SNP near integrin alpha 6 (ITGA6) reached genome-wide significance with PA (P = 1.80 x 10(-8)), whereas SNPs associated with Src kinase-associated phosphoprotein 1 (SKAP1), matrix metallopeptidase 12 (MMP12)/MMP13, catenin alpha 3 (CTNNA3), rho GTPase-activating protein 24 (ARHGAP24), angiopoietin 4 (ANGPT4), chromosome 11 open reading frame (C11orf30/EMSY), and exocyst complex component 4 (EXOC4) reached a threshold suggestive of association (P <= 1.49 x 10(-6)). In the meta-analysis of PA, loci in or near ITGA6, ANGPT4, MMP12/MMP13, C11orf30, and EXOC4 were significant (P <= 1.49 x 10(-6)). When a phenotype of any food allergy was used for meta-analysis, the C11orf30 locus reached genome-wide significance (P = 7.50 x 10(-11)), whereas SNPs associated with ITGA6, ANGPT4, MMP12/MMP13, and EXOC4 and additional C11orf30 SNPs were suggestive (P <= 1.49 x 10(-6)). Functional annotation indicated that SKAP1 regulates expression of CBX1, which colocalizes with the EMSY protein coded by C11orf30. Conclusion: This study identifies multiple novel loci as risk factors for PA and food allergy and establishes C11orf30 as a risk locus for both PA and food allergy. Multiple genes (C11orf30/EMSY, SKAP1, and CTNNA3) identified by this study are involved in epigenetic regulation of gene expression.

【 授权许可】

Free