全基因组关联研究和多人群荟萃分析鉴定了花生过敏的新易感基因位点，并确定 C11orf30/EMSY 为食物过敏的遗传危险因素。
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.
机构信息
Division of Dermatology, Department of Medicine, Queen's University, Kingston, and the Division of Experimental Medicine, Department of Medicine, McGill University, Montreal, Quebec, Canada.
Centre for Heart Lung Innovation, University of British Columbia, Vancouver, British Columbia, Canada.
出版信息
J Allergy Clin Immunol. 2018 Mar;141(3):991-1001. doi: 10.1016/j.jaci.2017.09.015. Epub 2017 Oct 10.
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), 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). In the meta-analysis of PA, loci in or near ITGA6, ANGPT4, MMP12/MMP13, C11orf30, and EXOC4 were significant (P ≤ 1.49 × 10). When a phenotype of any food allergy was used for meta-analysis, the C11orf30 locus reached genome-wide significance (P = 7.50 × 10), whereas SNPs associated with ITGA6, ANGPT4, MMP12/MMP13, and EXOC4 and additional C11orf30 SNPs were suggestive (P ≤ 1.49 × 10). 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.
背景
花生过敏（PA）是一种复杂的疾病，具有环境和遗传风险因素。先前，在候选基因研究中发现了丝聚蛋白（FLG）和 HLA 中的 PA 基因座，在全基因组关联研究和荟萃分析中发现了 HLA 中的基因座。
目的
我们旨在研究 PA 的遗传易感性。
方法
在加拿大人群中进行了一项全基因组关联研究，分析了 850 例病例和 926 例超对照受试者以及超过 780 万个经基因分型和推断的单核苷酸多态性（SNP），以鉴定 PA 的易感变体。通过来自加拿大、美国（n=2）、澳大利亚、德国和荷兰（n=2）的 7 项研究进行了 2 种表型（PA 和食物过敏）的荟萃分析。
结果
ITGA6 附近的一个 SNP 与 PA 达到全基因组显著水平（P=1.80×10），而与 Src 激酶相关磷酸蛋白 1（SKAP1）、基质金属蛋白酶 12/13（MMP12/MMP13）、连环蛋白 α3（CTNNA3）、Rho GTP 酶激活蛋白 24（ARHGAP24）、血管生成素 4（ANGPT4）、11 号染色体开放阅读框（C11orf30/EMSY）和外泌体复合物成分 4（EXOC4）相关的 SNP 达到了有意义的关联阈值（P≤1.49×10）。在 PA 的荟萃分析中，ITGA6、ANGPT4、MMP12/MMP13、C11orf30 和 EXOC4 附近或内部的基因座具有显著意义（P≤1.49×10）。当使用任何食物过敏的表型进行荟萃分析时，C11orf30 基因座达到全基因组显著水平（P=7.50×10），而与 ITGA6、ANGPT4、MMP12/MMP13 和 EXOC4 以及其他 C11orf30 SNP 相关的 SNP 具有提示意义（P≤1.49×10）。功能注释表明，SKAP1 调节 CBX1 的表达，而 CBX1 与 C11orf30 编码的 EMSY 蛋白共定位。
结论
本研究确定了多个新的基因座作为 PA 和食物过敏的风险因素，并确立了 C11orf30 作为 PA 和食物过敏的风险基因座。本研究鉴定的多个基因（C11orf30/EMSY、SKAP1 和 CTNNA3）参与了基因表达的表观遗传调控。
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