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

Yuka Asai; Aida Eslami; C Dorien van Ginkel; Loubna Akhabir; Ming Wan; George Ellis; Moshe Ben-Shoshan; David Martino; Manuel A Ferreira; Katrina Allen; Bruce Mazer; Hans de Groot; Nicolette W de Jong; Roy N Gerth van Wijk; Anthony E J Dubois; Rick Chin; Stephen Cheuk; Joshua Hoffman; Eric Jorgensen; John S Witte; Ronald B Melles; Xiumei Hong; Xiaobin Wang; Jennie Hui; Arthur W Bill Musk; Michael Hunter; Alan L James; Gerard H Koppelman; Andrew J Sandford; Ann E Clarke; Denise Daley

doi:10.1016/j.jaci.2017.09.015

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

J Allergy Clin Immunol. 2018 Mar;141(3):991-1001. doi: 10.1016/j.jaci.2017.09.015. Epub 2017 Oct 10.

Authors

Yuka Asai¹, Aida Eslami², C Dorien van Ginkel³, Loubna Akhabir², Ming Wan², George Ellis², Moshe Ben-Shoshan⁴, David Martino⁵, Manuel A Ferreira⁶, Katrina Allen⁵, Bruce Mazer⁴, Hans de Groot⁷, Nicolette W de Jong⁸, Roy N Gerth van Wijk⁸, Anthony E J Dubois³, Rick Chin⁹, Stephen Cheuk¹⁰, Joshua Hoffman¹¹, Eric Jorgensen¹², John S Witte¹¹, Ronald B Melles¹³, Xiumei Hong¹⁴, Xiaobin Wang¹⁴, Jennie Hui¹⁵, Arthur W Bill Musk¹⁶, Michael Hunter¹⁷, Alan L James¹⁸, Gerard H Koppelman³, Andrew J Sandford², Ann E Clarke¹², Denise Daley¹⁹

Affiliations

¹ Division of Dermatology, Department of Medicine, Queen's University, Kingston, and the Division of Experimental Medicine, Department of Medicine, McGill University, Montreal, Quebec, Canada.
² Centre for Heart Lung Innovation, University of British Columbia, Vancouver, British Columbia, Canada.
³ 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.
⁴ Division of Allergy and Immunology, Department of Pediatrics, Montreal Children's Hospital, Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada.
⁵ Murdoch Children's Research Institute, Royal Children's Hospital, University of Melbourne, Melbourne, Australia.
⁶ QIMR Berghofer Medical Research Institute, Brisbane, Australia.
⁷ Department of Pediatric Allergology, Diaconessenhuis Voorburg, Reinier de Graaf Gasthuis, Delft, The Netherlands.
⁸ Erasmus MC, Department of Allergology, Rotterdam, The Netherlands.
⁹ Division of Rheumatology, Department of Medicine, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.
¹⁰ Private Practice, Calgary, Alberta.
¹¹ Department of Epidemiology and Biostatistics, University of California, San Francisco, Calif.
¹² Division of Research, Kaiser Permanente Northern California, Oakland, Calif.
¹³ Department of Ophthalmology, Kaiser Permanente Northern California, Redwood City Medical Center, Redwood City, Calif.
¹⁴ 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.
¹⁵ School of Population Health, University of Western Australia, Australia and Pathology and Laboratory Medicine, University of Western Australia, Perth, Australia.
¹⁶ Department of Respiratory Medicine, Sir Charles Gairdner Hospital, and School of Population Health, University of Western Australia, Perth, Australia.
¹⁷ School of Population Health, University of Western Australia, Perth, Australia.
¹⁸ Department of Pulmonary Physiology and Sleep Medicine, Sir Charles Gairdner Hospital, School of Medicine and Pharmacology, University of Western Australia, Perth, Australia.
¹⁹ Centre for Heart Lung Innovation, University of British Columbia, Vancouver, British Columbia, Canada. Electronic address: denise.daley@hli.ubc.ca.

PMID: 29030101
DOI: 10.1016/j.jaci.2017.09.015

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.

Keywords: C11orf30; EMSY; Peanut allergy; epigenetics; food allergy; genome-wide association study; meta-analysis.

Publication types

Meta-Analysis
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Chromobox Protein Homolog 5
Epigenesis, Genetic*
Female
Filaggrin Proteins
Genetic Loci*
Genome-Wide Association Study*
Humans
Male
Neoplasm Proteins / genetics*
Nuclear Proteins / genetics*
Peanut Hypersensitivity / epidemiology
Peanut Hypersensitivity / genetics*
Peanut Hypersensitivity / metabolism
Phosphoproteins / biosynthesis
Phosphoproteins / genetics
Polymorphism, Single Nucleotide*
Repressor Proteins / genetics*
Risk Factors
alpha Catenin / biosynthesis
alpha Catenin / genetics

Substances

CBX1 protein, human
CTNNA3 protein, human
EMSY protein, human
FLG protein, human
Filaggrin Proteins
Neoplasm Proteins
Nuclear Proteins
Phosphoproteins
Repressor Proteins
SKAP1 protein, human
alpha Catenin
Chromobox Protein Homolog 5

Grants and funding

RC2 AG036607/AG/NIA NIH HHS/United States