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Journal of Allergy and Clinical Immunology

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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 - 07/03/18

Doi : 10.1016/j.jaci.2017.09.015 
Yuka Asai, MD, MSc a, ∗, Aida Eslami, PhD b, ∗, C. Dorien van Ginkel, BSc c, Loubna Akhabir, PhD b, Ming Wan, BSc b, George Ellis, BSc b, Moshe Ben-Shoshan, MD, MSc d, David Martino, PhD e, Manuel A. Ferreira, PhD f, Katrina Allen, MD, PhD e, Bruce Mazer, MD d, Hans de Groot, MD, PhD g, Nicolette W. de Jong, PhD h, Roy N. Gerth van Wijk, MD, PhD h, Anthony E.J. Dubois, MD, PhD c, Rick Chin, MSc i, Stephen Cheuk, MD j, Joshua Hoffman, PhD k, Eric Jorgensen, PhD l, John S. Witte, PhD m, Ronald B. Melles, MD n, Xiumei Hong, MD, PhD o, Xiaobin Wang, MD, MPH, ScD o, Jennie Hui, PhD p, Arthur W. (Bill) Musk, FRACP q, Michael Hunter, PhD r, Alan L. James, FRACP s, Gerard H. Koppelman, MD, PhD c, Andrew J. Sandford, PhD b, Ann E. Clarke, MD, MSc l, ‡, Denise Daley, PhD b, ⁎, ‡
a Division of Dermatology, Department of Medicine, Queen's University, Kingston, and the Division of Experimental Medicine, Department of Medicine, McGill University, Montreal, Quebec, Canada 
b Centre for Heart Lung Innovation, University of British Columbia, Vancouver, British Columbia, Canada 
c University of Groningen, University Medical Center Groningen, Department of Pediatric Pulmonology and Pediatric Allergology and University of Groningen, University Medical Center Groningen, GRIAC Research Institute, Groningen, The Netherlands 
d Division of Allergy and Immunology, Department of Pediatrics, Montreal Children's Hospital, Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada 
e Murdoch Children's Research Institute, Royal Children's Hospital, University of Melbourne, Melbourne, Australia 
f QIMR Berghofer Medical Research Institute, Brisbane, Australia 
g Department of Pediatric Allergology, Diaconessenhuis Voorburg, Reinier de Graaf Gasthuis, Delft, The Netherlands 
h Erasmus MC, Department of Allergology, Rotterdam, The Netherlands 
i Division of Rheumatology, Department of Medicine, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada 
j Private Practice, Calgary, Alberta 
k Department of Epidemiology and Biostatistics, University of California, San Francisco, Calif 
l Division of Research, Kaiser Permanente Northern California, Oakland, Calif 
m Department of Epidemiology and Biostatistics, University of California, San Francisco, Calif 
n Department of Ophthalmology, Kaiser Permanente Northern California, Redwood City Medical Center, Redwood City, Calif 
o Department of Population, Family and Reproductive Health, Center on the Early Life Origins of Disease, Johns Hopkins University Bloomberg School of Public Health, Baltimore, Md 
p School of Population Health, University of Western Australia, Australia and Pathology and Laboratory Medicine, University of Western Australia, Perth, Australia 
q Department of Respiratory Medicine, Sir Charles Gairdner Hospital, and School of Population Health, University of Western Australia, Perth, Australia 
r School of Population Health, University of Western Australia, Perth, Australia 
s Department of Pulmonary Physiology and Sleep Medicine, Sir Charles Gairdner Hospital, School of Medicine and Pharmacology, University of Western Australia, Perth, Australia 

∗Corresponding author: Denise Daley, PhD, Centre for Heart Lung Innovation, St Paul's Hospital, Rm 166, 1081 Burrard St, Vancouver, British Columbia, V6Z 1Y6 Canada.Centre for Heart Lung InnovationSt Paul's HospitalRm 166, 1081 Burrard StVancouverBritish ColumbiaV6Z 1Y6Canada

Abstract

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 α6 (ITGA6) reached genome-wide significance with PA (P = 1.80 × 10−8), whereas SNPs associated with Src kinase–associated phosphoprotein 1 (SKAP1), matrix metallopeptidase 12 (MMP12)/MMP13, catenin α3 (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 × 10−6). In the meta-analysis of PA, loci in or near ITGA6, ANGPT4, MMP12/MMP13, C11orf30, and EXOC4 were significant (P ≤ 1.49 × 10−6). When a phenotype of any food allergy was used for meta-analysis, the C11orf30 locus reached genome-wide significance (P = 7.50 × 10−11), whereas SNPs associated with ITGA6, ANGPT4, MMP12/MMP13, and EXOC4 and additional C11orf30 SNPs were suggestive (P ≤ 1.49 × 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.

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Key words : Peanut allergy, food allergy, genome-wide association study, meta-analysis, EMSY, C11orf30, epigenetics

Abbreviations used : ANGPT4, ARHGAP24, CanPAR, CFA, CHCHD3, C11orf30, CNV, CTNNA3, eQTL, EXOC4, FLG, GERA, GWAS, ITGA6, MAF, MMP, OR, PA, QC, QQ, SKAP1, SNP, UFA


Plan


 Supported by the Allergy, Genes, and Environment Network of Centres of Excellence (AllerGen NCE); the Canadian Institutes of Health Research; Canadian Research Chairs Program (salary award to D. Daley); the Natural Sciences and Engineering Research Council; the Michael Smith Foundation for Health Research/AllerGen NCE post-doctoral research fellowship awards (A.E.); the Division of Experimental Medicine Entrance Fellowship (Y.A.); the Montreal Children's Hospital Foundation; the McGill University Health Centre Foundation; the Canadian Dermatology Foundation; the Canadian Allergy, Asthma and Immunology Foundation; the Canadian Society of Allergy and Clinical Immunology; the National Institutes of Health (grant no. CA112355 awarded to J.S.W. and RC2 AG036607 awarded to C.A.S. and N.J.R.); HealthWay; the National Health and Medical Research Council (Australia); the Australian Research Council; and the US Department of Defense (grant no. W81XWH-10-1-0487 to K.A.). C.D.v.G., A.E.J.D., and G.H.K. received an unrestricted grant from the Nutricia Research Foundation to complete the Dutch GENEVA cohort. The Dutch IDEAL cohort of N.W.d.J., H.d.G., R.G.v.W., and A.E.J.D. was supported by the Dutch Technology Foundation STW, which is part of the Netherlands Organisation for Scientific Research (NOW) and partly funded by the Ministry of Economic Affairs (project number 11868) and the Food Allergy Foundation, Siemens Healthcare Diagnostics, HAL Allergy, Intersnack the Netherlands B.V., ALK-Abelló B.V., and the Netherlands Anaphylaxis Network. The Genotype-Tissue Expression (GTEx) Project was supported by the Common Fund of the Office of the Director of the National Institutes of Health, and by the National Cancer Institute; National Human Genome Research Institute; National Heart, Lung, and Blood Institute; National Institute on Drug Abuse; National Institute of Mental Health; and National Institute of Neurological Disorders and Stroke.
 Disclosure of potential conflict of interest: Y. Asai and A. E. Clarke have received a grant from the Allergy, Genes, and Environment Network of Centres of Excellence (AllerGEN NCE) and has received travel support from the Canadian Institutes of Health Research (CIHR). C. D. van Ginkel has received grants from JC de Cock Stichting and the Nutricia Research Foundation. K. Allen has received consulting fees or honoraria from Nestle and Thermo Fisher and has consultant arrangements with Before Brands. B. Mazer and D. Daley have received grants from ALLERGEN-NCE and the Canadian Institutes of Health Research (CIHR). R. N. Gerth van Wijk has received a grant from STW. S. Cheuk has consultant arrangements with Novartis, Sanofi, Graceway, Merck, and Pfizer and has received payment for lectures from GlaxoSmithKline, Sanofi, Graceway, Pfizer, Merck, Novartis, and Pediapharm. G. H. Koppelman has received grants from the Lung Foundation of the Netherlands, TEVA, UBBO Emius Foundation, TETRI Foundation, and GlaxoSmithKline. The rest of the authors declare that they have no relevant conflicts of interest.


© 2017  The Authors. Publié par Elsevier Masson SAS. Tous droits réservés.
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Vol 141 - N° 3

P. 991-1001 - mars 2018 Retour au numéro
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