Amo Gemma, Martí Manuel, García-Menaya Jesús M, Cordobés Concepción, Cornejo-García José A, Blanca-López Natalia, Canto Gabriela, Doña Inmaculada, Blanca Miguel, Torres María José, Agúndez José A G, García-Martín Elena
University Institute of Molecular Pathology Biomarkers, UEx, Cáceres, Spain.
ARADyAL Instituto de Salud Carlos III, Cáceres, Spain.
Front Genet. 2019 Jun 25;10:582. doi: 10.3389/fgene.2019.00582. eCollection 2019.
The prevalence of allergic diseases and drug hypersensitivity reactions (DHRs) during recent years is increasing. Both, allergic diseases and DHRs seem to be related to an interplay between environmental factors and genetic susceptibility. In recent years, a large effort in the elucidation of the genetic mechanisms involved in these disorders has been made, mostly based on case-control studies, and typically focusing on isolated SNPs. These studies provide a limited amount of information, which now can be greatly expanded by the complete coverage that Next Generation Sequencing techniques offer. In this study, we analyzed the promoters of sixteen genes related to the Vitamin D pathway and the high-affinity IgE receptor, including , and . The study group was composed of patients with allergic rhinitis plus asthma (AR+A), patients with hypersensitivity to beta-lactams (BLs), to NSAIDs including selective hypersensitivity (SH) and cross-reactivity (CR), and healthy controls without antecedents of atopy or adverse drug reactions. We identified 148 gene variations, 43 of which were novel. Multinomial analyses revealed that three SNPs corresponding to the genes (rs36233990 and rs2070901), and (rs3733359), displayed significant associations and, therefore, were selected for a combined dataset study in a cohort of 2,476 individuals. The strongest association was found with the promoter rs36233990 SNP that alters a transcription factor binding site. This SNP was over-represented among AR+A patients and among patients with IgE-mediated diseases, as compared with control individuals or with the rest of patients in this study. Classification models based on the above-mentioned SNPs were able to predict correct clinical group allocations in patients with DHRs, and patients with IgE-mediated DHRs. Our findings reveal gene promoter SNPs that are significant predictors of drug hypersensitivity, thus reinforcing the hypothesis of a genetic predisposition for these diseases.
近年来，过敏性疾病和药物过敏反应（DHRs）的患病率正在上升。过敏性疾病和DHRs似乎都与环境因素和遗传易感性之间的相互作用有关。近年来，人们在阐明这些疾病所涉及的遗传机制方面付出了巨大努力，主要基于病例对照研究，并且通常聚焦于单个单核苷酸多态性（SNPs）。这些研究提供的信息有限，而现在通过下一代测序技术提供的全面覆盖可以极大地扩展这些信息。在本研究中，我们分析了与维生素D途径和高亲和力IgE受体相关的16个基因的启动子，包括……。研究组由过敏性鼻炎合并哮喘（AR+A）患者、对β-内酰胺类（BLs）过敏患者、对非甾体抗炎药（包括选择性过敏（SH）和交叉反应（CR））过敏患者以及无特应性或药物不良反应史的健康对照组成。我们鉴定出148个基因变异，其中43个是新发现的。多项分析显示，对应于基因……（rs36233990和rs2070901）以及……（rs3733359）的三个SNPs显示出显著关联，因此被选入一个由2476名个体组成的队列进行联合数据集研究。发现与启动子rs36233990 SNP的关联最强，该SNP改变了一个转录因子结合位点。与对照组个体或本研究中的其他患者相比，该SNP在AR+A患者和IgE介导疾病患者中过度出现。基于上述SNPs的分类模型能够预测DHRs患者以及IgE介导的DHRs患者的正确临床分组。我们的发现揭示了基因启动子SNPs是药物过敏的重要预测指标，从而强化了这些疾病存在遗传易感性的假说。
