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
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 &agr;6 (ITGA6) reached genome wide significance with PA (P=1.80x10 8) whereas SNPs associated with Src kinase associated phosphoprotein 1 (SKAP1) matrix metallopeptidase 12 (MMP12)/MMP13, catenin &agr;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<=1.49x10 6) In the meta analysis of PA, loci in or near ITGA6, ANGPT4, MMP12/MMP13, C11orf30, and EXOC4 were significant (P<=1.49x10 6) When a phenotype of any food allergy was used for meta analysis, the C11orf30 locus reached genome wide significance (P=7.50x10 11) whereas SNPs associated with ITGA6, ANGPT4, MMP12/MMP13, and EXOC4 and additional C11orf30 SNPs were suggestive (P<=1.49x10 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.
The Journal of allergy and clinical immunology