TY - JOUR
T1 - 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
AU - Asai, Yuka
AU - Eslami, Aida
AU - van Ginkel, C. Dorien
AU - Akhabir, Loubna
AU - Wan, Ming
AU - Ellis, George
AU - Ben-Shoshan, Moshe
AU - Martino, David
AU - Ferreira, Manuel A.
AU - Allen, Katrina
AU - Mazer, Bruce
AU - de Groot, Hans
AU - de Jong, Nicolette W.
AU - Gerth van Wijk, Roy N.
AU - Dubois, Anthony E.J.
AU - Chin, Rick
AU - Cheuk, Stephen
AU - Hoffman, Joshua
AU - Jorgensen, Eric
AU - Witte, John S.
AU - Melles, Ronald B.
AU - Hong, Xiumei
AU - Wang, Xiaobin
AU - Hui, Jennie
AU - Musk, Arthur W.
AU - Hunter, Michael
AU - James, Alan L.
AU - Koppelman, Gerard H.
AU - Sandford, Andrew J.
AU - Clarke, Ann E.
AU - Daley, Denise
PY - 2018/3
Y1 - 2018/3
N2 - 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.
AB - 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.
KW - C11orf30
KW - EMSY
KW - Epigenetics
KW - Food allergy
KW - Genome-wide association study
KW - Meta-analysis
KW - Peanut allergy
UR - http://www.scopus.com/inward/record.url?scp=85033374056&partnerID=8YFLogxK
U2 - 10.1016/j.jaci.2017.09.015
DO - 10.1016/j.jaci.2017.09.015
M3 - Article
VL - 141
SP - 991
EP - 1001
JO - The Journal of Allergy and Clinical Immunology
JF - The Journal of Allergy and Clinical Immunology
SN - 0091-6749
IS - 3
ER -