小麦依赖－运动诱发严重过敏反应（WDEIA）的分子遗传学机制与动物模型研究

Wheat-dependence exercise-induced anaphylaxis (WDEIA) is a special type of food allergy, which is a current international research hotspot, but the genetic factors were not fully explored by researchers. In our previous studies, we found that the polymorphisms of IL-4-C590T and HLA-RB1*1302 might be associated with the risk of WDEIA. With the development of genomics and the accumulation of samples. We intend to explore new genetic susceptibility markers in the whole genome. In this study, 400 patients with WDEIA will be enrolled, and the associated single nucleotide polymorphisms (SNPs) with WDEIA susceptibility will be screened from 900,000 SNPs by genome-wide association analysis and then be validated. The function of SNPs located in different regions of genes will be predicted, which may be involved in the process of gene expression regulation. The mechanism will be studied using real-time quantitative PCR and luciferase reporter gene. The results may show the Genetic susceptibility with WDEIA in Chinese population. In addition, the WDEIA mouse model is planned to be constructed by oral gavage with gliadin for sensetization，and by exercise-assisted oral gavage for challenge. In a word, the research of molecular genetic mechanism is expected to lead us to find the accurate diagnosis and treatment target of WDEIA.

小麦依赖－运动诱发严重过敏反应（WDEIA）是食物过敏的特殊类型，当前国际上的研究热点，但对其遗传因素的研究不多。本课题组在前期的研究中，发现IL-4-C590T等两种基因多态性可能与WDEIA发病风险相关。随着基因组学的发展和样本量的积累，本课题组拟在全基因组范围探索新的遗传易感性标志物。本项目拟纳入400例WDEIA患者，通过全基因组关联分析及验证，从90多万个单核苷酸多态性（SNPs）中高质量地筛选WDEIA易感性的关联SNPs。对位于基因不同区域的关联SNPs进行功能预测，并通过实时定量PCR、荧光素酶报告基因等方法研究这些SNPs在基因表达调控过程中的功能，研究成果将在国际上首次较全面地揭示中国汉族人群WDEIA的遗传易感性。并创新性采用小麦醇溶蛋白经口灌胃途径致敏，以及运动辅助激发的方法构建WDEIA小鼠模型。以期通过分子遗传学研究，寻找WDEIA精准诊断治疗的靶点。

小麦依赖-运动诱发严重过敏反应（WDEIA）是一种具有潜在致死风险的、严重的IgE介导的食物过敏。本课题首次在中国汉族人群中开展WDEIA的GWAS研究，构建了中国汉族人群WDEIA与正常对照的全基因组关联分析数据库。发现1个与WDEIA相关的新易感区域13q34，以及两个提示易感位点。既往GWAS报道的花生过敏易感的HLA基因区域与WDEIA无显著相关性，也未发现风险性的单倍型。LYST基因的位点rs7548449与WDEIA发病有相关性，rs7548449等位基因G到T的变异可导致基因转录活性下调，导致LYST基因mRNA表达降低，且血清蛋白浓度也同时降低。这一发现为WDEIA发病机制的研究提供了新的证据。IL18基因内的rs1946518位点、IL18RAP基因内的rs11465670位点多态性与中国汉族人群WDEIA易感性显著相关，IL18基因区域存在WDEIA易感的风险性单倍型。且IL18基因rs1946518位点GT基因型与血清IL18水平、总IgE的上调相关，增加了WDEIA的风险。本研究深化了对WDEIA的遗传学基础的认识，同时为WDEIA的发病机制研究提供新的证据。