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.

中文翻译：

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多族群的全基因组关联研究和荟萃分析确定了花生过敏的新基因座，并将C11orf30 / EMSY确定为食物过敏的遗传危险因素

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。以前，在候选基因研究中已在丝蛋白（FLG）和HLA中鉴定了PA位点，而在全基因组关联研究和荟萃分析中鉴定了HLA中的基因座。

客观的

我们试图调查对PA的遗传易感性。

方法

在全基因组关联研究中分析了850例病例和926个高对照受试者以及超过780万个基因分型和估算的单核苷酸多态性（SNP），以确定加拿大人群中PA的易感性变异。通过使用来自加拿大，美国（n = 2），澳大利亚，德国和荷兰（n = 2）人群的7项研究，对2个表型（PA和食物过敏）进行了荟萃分析。

结果

整合素α6 （ITGA6）附近的SNP在PA中达到全基因组意义（P  = 1.80×10 ^-8），而与Src激酶相关的磷蛋白1 （SKAP1），基质金属肽酶12 （MMP12）/ MMP13和连环蛋白α3相关的SNP （CTNNA3），ρ-GTP酶激活蛋白24 （ARHGAP24） ，血管生成素4 （ANGPT4），11号染色体开放读码框（C11orf30 / EMSY） ，和exocyst复杂部件4 （EXOC4）达到关联（的阈值暗示P  ≤1.49× 10 ^-6）。在PA的荟萃分析中，ITGA6或附近的基因座，ANGPT4，MMP12 / MMP13，C11orf30，和EXOC4均显著（P  ≤1.49×10 ^-6）。当将任何食物过敏的表型用于荟萃分析时，C11orf30基因座达到了全基因组意义（P  = 7.50×10 ^-11），而与ITGA6，ANGPT4，MMP12 / MMP13和EXOC4相关的SNP和其他C11orf30 SNP均提示（P  ≤1.49×10 ^-6）。功能注释表明，SKAP1调节以下基因的表达CBX1，与C11orf30编码的EMSY蛋白共定位。

结论

这项研究确定了多个新基因位点为PA和食物过敏的危险因素，并将C11orf30建立为PA和食物过敏的风险源。本研究确定的多个基因（C11orf30 / EMSY，SKAP1和CTNNA3）参与基因表达的表观遗传调控。