Mechanisms of genetic risk at 2p23 in Eosinophilic Esophagitis

摘要 嗜酸性粒细胞性食管炎（EoE）是一种慢性、过敏性胃肠道疾病， 从童年到成年持续的嗜酸性粒细胞增多症。EoE领域的核心问题之一， 一般来说，是为了了解为什么个人发展某些表现的过敏性疾病，如EoE。 我们最近发现，除了过敏性致敏遗传危险因素，EoE易感性与 在2 p23的遗传位点，编码CAPN 14基因和calpain-14蛋白。这种遗传联系 在多个队列中重复，以及最近的一项独立研究，增加了对 2 p23基因连锁。Calpain-14以前没有在我们最近的新数据集之外进行过研究;然而， 经典钙蛋白酶的其它成员的已知底物包括与 过敏反应我们确定CAPN 14作为EoE疾病活动的功能动态上调 和遗传单倍型，以及上皮细胞暴露于IL-13后。在初步研究中， 确定了一组内含子和基因内遗传变异，最有可能是EoE增加的原因 风险我们还生成了证实钙蛋白酶-14在疾病诱导和免疫调节中的调节作用的数据。 修复.利用这些结果，我们提出了一套旨在测试我们的中心假设， EoE的发生是由遗传危险因素介导的，包括全身性特应性的相互作用 易感基因座（11 q13/5 q22）和涉及CAPN 14的EoE食管反应。我们将测试这个 通过关注解释基因型依赖性调节的功能机制， CAPN 14表达（目的1）和钙蛋白酶-14的下游靶点和调节作用（目的2）。基于 基于我们的假设，即钙蛋白酶-14在IL-13介导的炎症中起作用，我们将评估钙蛋白酶-14在IL-13介导的炎症中的作用。 通过诊断的统计学考虑，增加2 p23遗传变异的临床预测效用 与过敏性鼻炎、哮喘或特应性皮炎和其他关键的特应性相关的遗传基因座（目的3）。这些 实验是及时的，因为它们解决了最近NIH研讨会概述的未满足的医疗需求（见 Bochner等人JACI; PMCID：PMC 3432981和PA-15-027）。通过一组三个目标的测试， 互补的假设，我们提出了一个机会，解剖一个重要的疾病，使真实的 对功能基因组学、生物化学、炎症和相互作用的全球理解的进展 通过2 p23和钙蛋白酶-14增加EoE风险的机制。

Abstract Eosinophilic Esophagitis (EoE) is a chronic, allergic gastrointestinal disorder marked by esophageal eosinophilia persisting from childhood into adulthood. One of the central questions in the EoE field, and allergy in general, is to understand why individuals develop certain manifestations of allergic disease, such as EoE. We have recently found that in addition to allergic sensitization genetic risk factors, EoE susceptibility is linked to a genetic locus at 2p23, encoding the CAPN14 gene and calpain-14 protein. This genetic linkage has been replicated in multiple cohorts, as well as a recent independent study, adding credence to the importance of the 2p23 genetic linkage. Calpain-14 has not been previously studied outside of our recent new dataset; however, known substrates for other members of the classical calpains include inflammatory mediators relevant for allergic responses. We identified CAPN14 as dynamically up-regulated as a function of EoE disease activity and genetic haplotype, as well as after exposure of epithelial cells to IL-13. In preliminary studies, we have identified a set of intronic and intragenic genetic variants that are most likely to be causal for increased EoE risk. We have also generated data substantiating a regulatory role for calpain-14 in both disease induction and repair. Using these results, we propose a set of aims designed to test our central hypothesis that the development of EoE is mediated by genetic risk factors that include the interplay of generalized atopy susceptibility loci (11q13/5q22) and an EoE esophageal response involving CAPN14. We will test this hypothesis by focusing on functional mechanisms that account for the genotype-dependent regulation of CAPN14 expression (Aim 1) and the downstream targets and regulatory role of calpain-14 (Aim 2). Based upon our hypothesis that calpain-14 functions in the context of IL-13-mediated inflammation, we will assess the increased clinical predictive utility of genetic variants at 2p23 through the statistical consideration of diagnosis with allergic rhinitis, asthma, or atopic dermatitis and other key atopy associated genetic loci (Aim 3). These experiments are timely, as they address an unmet medical need as outlined by a recent NIH workshop (see Bochner et al JACI; PMCID: PMC3432981 and PA-15-027). Through a set of three aims testing complementary hypotheses, we present an opportunity to dissect an important disease and make real progress towards a global understanding of the functional genomic, biochemical, inflammatory, and interactive mechanisms that increase risk of EoE through 2p23 and calpain-14.