Table_6_Investigation of the Possible Role of Tie2 Pathway and TEK Gene in Asthma and Allergic Conjunctivitis.xlsx

Tie2, coded by the TEK gene, is a tyrosine kinase receptor and plays a central role in vascular stability. It was suggested that variations in the TEK gene might influence the susceptibility to asthma and allergic conjunctivitis. The aim of this study was to further investigate these suggestions, involving different populations and to study the Tie2 related pathway on a mouse model of asthma. The discovery, stage I cohort involved 306 patients with moderate and severe allergic rhinitis, the stage II study consisted of four cohorts, namely, adult and pediatric asthmatics and corresponding controls. Altogether, there were 1,258 unrelated individuals in these cohorts, out of which 63.9% were children and 36.1% were adults. In stage I, 112 SNPs were screened in the TEK gene of the patients in order to search for associations with asthma and allergic conjunctivitis. The top associated SNPs were selected for association studies on the replication cohorts. The rs3824410 SNP was nominally associated with a reduced risk of asthma in the stage I cohort and with severe asthma within the asthmatic population (p=0.009; OR=0.48) in the replication cohort. In the stage I study, 5 SNPs were selected in conjunctivitis. Due to the low number of adult patients with conjunctivitis, only children were involved in stage II. Within the asthmatic children, the rs622232 SNP was associated with conjunctivitis in boys in the dominant model (p=0.004; OR=4.76), while the rs7034505 showed association to conjunctivitis in girls (p=0.012; OR=2.42). In the lung of a mouse model of asthma, expression changes of 10 Tie2 pathway-related genes were evaluated at three points in time. Eighty percent of the selected genes showed significant changes in their expressions at least at one time point during the process, leading from sensitization to allergic airway inflammation. The expressions of both the Tek gene and its ligands showed a reduced level at all time points. In conclusion, our results provide additional proof that the Tie2 pathway, the TEK gene and its variations might have a role in asthma and allergic conjunctivitis. The gene and its associated pathways can be potential therapeutic targets in both diseases.

Tie2基因编码的Tie2是一种酪氨酸激酶受体，其在血管稳定性中发挥着核心作用。研究表明，TEK基因的变异可能影响哮喘和过敏性结膜炎的易感性。本研究旨在进一步探究这些假设，涉及不同人群，并在哮喘小鼠模型上研究Tie2相关通路。第一阶段的研究涉及306名患有中重度过敏性鼻炎的患者，第二阶段的研究包括四个队列，即成年和儿童哮喘患者及其对照组。总计，这些队列中有1,258名无关个体，其中63.9%为儿童，36.1%为成人。在第一阶段，对患者的TEK基因进行了112个单核苷酸多态性（SNP）的筛查，以寻找与哮喘和过敏性结膜炎的相关性。在验证队列中，选出了与哮喘和过敏性结膜炎最相关的SNP进行关联研究。在第一阶段队列中，rs3824410 SNP与哮喘的降低风险相关（p=0.009；OR=0.48），在验证队列中，与哮喘患者群体中的重症哮喘相关。在第一阶段研究中，选取了5个与结膜炎相关的SNP。由于结膜炎成年患者数量较少，第二阶段仅涉及儿童。在哮喘儿童中，rs622232 SNP在显性模型中与男孩的结膜炎相关（p=0.004；OR=4.76），而rs7034505与女孩的结膜炎相关（p=0.012；OR=2.42）。在哮喘小鼠模型的肺部，评估了10个Tie2通路相关基因在三个时间点的表达变化。所选基因中有80%在至少一个时间点表现出其表达水平发生了显著变化，从致敏到过敏性气道炎症的过程。Tek基因及其配体的表达在所有时间点均显示出降低水平。总之，我们的研究结果为Tie2通路、TEK基因及其变异可能在哮喘和过敏性结膜炎中发挥作用提供了额外的证据。这些基因及其相关通路可能成为这两种疾病的潜在治疗靶点。