The Genetics and Genomics of Allergic Rhinitis

描述（由申请人提供）：过敏性鼻炎（AR）是一种ige介导的上呼吸道炎症，可引起鼻眼充血、瘙痒、鼻漏和打喷嚏。AR俗称花粉热、季节性过敏和过敏症，是最常见的慢性疾病之一，影响10-30%的成年人和40%的儿童。相对于哮喘的遗传学，AR的遗传学研究还不够充分。我们假设AR存在重要的遗传决定因素，这些基因可以在高危人群中使用综合基因组方法进行鉴定，并且这些基因在网络中相互作用以调节AR患者中过敏原诱导的细胞因子的产生。我们将通过三个具体目标来检验这一假设。首先，我们将对改变变应性鼻炎风险的单核苷酸多态性（SNP）进行全基因组分析，并在两个独立的队列中重复我们的发现。其次，我们将在哮喘受试者中试点并实施鼻上皮收集方案，利用这种鼻上皮资源获得基因表达谱，并利用鼻上皮和CD4+淋巴细胞的表达数据进行变应性鼻炎的综合基因组分析。第三，我们将进行荧光素酶报告基因检测，并测量过敏原诱导的细胞因子增殖，以验证鉴定的遗传变异的生物学相关性，并建立模型网络，将我们的实验数据整合到免疫途径的背景下。我们预计，从这一建议中确定的功能变异将阐明免疫途径，并确定疾病预测和治疗干预的目标。除了其科学相关性外，拟议的项目还概述了一个职业发展计划，该计划将培训首席研究员成为过敏性疾病遗传学和基因组学方面的独立研究者。

DESCRIPTION (provided by applicant): Allergic rhinitis (AR) is an IgE-mediated inflammation of the upper airway that causes naso-ocular congestion and pruritus, rhinorrhea, and sneezing. Colloquially referred to as hay fever, seasonal allergies, and allergies, AR is one of the most common chronic diseases, affecting 10-30% of adults and 40% of children. The genetics of AR have been understudied relative to those of asthma. We hypothesize that there are significant genetic determinants of AR, that these genes can be identified using integrative genomic approaches in at-risk populations, and that these genes interact in networks to regulate allergen-induced cytokine production in AR patients. We will test this hypothesis via three specific aims. First, we will perform a genome-wide analysis for single nucleotide polymorphisms (SNP) that alter risk for allergic rhinitis and replicate our findings in two independent cohorts. Second, we will pilot and implement a nasal epithelium collection protocol in asthmatic subjects, obtain gene expression profiles using this nasal epithelium resource, and perform integrative genomic analysis of allergic rhinitis using expression data from nasal epithelium and CD4+ lymphocytes. Third, we will perform luciferase reporter assays and measure allergen-induced cytokine proliferation to validate the biologic relevance of identified genetic variants, and model networks to integrate our experimental data within the context of immunologic pathways. We anticipate that functional variants identified from this proposal will elucidate immunologic pathways and define targets for disease prediction and therapeutic intervention. In addition to its scientific relevance, the proposed project outlines a career development plan that will train the principal investigator to become an independent investigator in the genetics and genomics of allergic disease. PROJECT NARRATIVE / PUBLIC HEALTH RELEVANCE Allergic rhinitis is one of the most common chronic diseases in children and adults.2 Allergic rhinitis is associated with decreased work productivity,4 poor school attendance,4 increased asthma severity,1 and higher rates of asthma-related hospitalization.5 We will use genetic and genomic approaches to identify novel disease-modifying genetic variants in allergic rhinitis that may be targeted for therapeutic intervention.