组胺H1受体基因功能性SNP对地氯雷他定治疗慢性荨麻疹疗效的影响

Chronic urticaria(CU) is a common allergic disease in the clinic. Because of its severe itching characteristics and recurrent, it affects the quality of life of patients. Second-generation H1-antihistamines are the first-line treatment for chronic urticaria, but the individual therapeutic effect is difference. In current study, we focused on the HRH1, a gene of the receptor of antihistamines, and a commonly used second-generation antihistamines- desloratadine, as the observation drug. Firstly, we will screen association between the functional variants of influenced H1 receptor protein which is encoded by HRH1 gene, and then the location and frequency of HRH1 gene SNPs in coding region will validate by direct sequencing from the genome DNA of chronic urticaria subjects in south Chinese Han population. Then, we will incorporate functional predictions of HRH1 gene SNPs in coding region using the methods of haplotype construction and bioinformatics softwares. And then confirm the SNPs association with the desloratadine therapy by case-control assay. After that, we will select the functional SNPs to carry out a series of functional experiments including the construction of genotype carrier, transfection and cell biology and so on. We will determinate the biologic effects of the functional HRH1SNPs. Finally, the purpose of this study is to find HRH1 functional SNPs which associated with the desloratadine therapy of CU from the genetic level, so as to provide a basis for individual clinical administration of CU.

慢性荨麻疹是一种常见的过敏性疾病，目前病因不明，由于其剧烈瘙痒、反复发作等特点，严重影响患者的生活质量。第二代抗组胺药是治疗慢性荨麻疹的一线用药，但疗效存在明显的个体差异。本研究拟锁定抗组胺药物结合受体—组胺H1受体编码基因HRH1为候选基因，以常用的第二代抗组胺药地氯雷他定为观察药物，首先筛选能影响H1受体蛋白表达或功能的SNP，并对500例中国南部汉族慢性荨麻疹患者基因组DNA进行HRH1基因编码序列区测序，明确其SNP分布情况后，利用单倍型构建、生物信息学和关联分析等方法发现HRH1潜在功能性SNP，再结合临床疗效进行关联分析，寻找与疗效相关的功能性SNP。最后选取相应功能性SNP，运用基因型载体构建、转染及细胞生物学等方法，证实HRH1功能性SNP的生物学效应。旨在从遗传学层面来寻找并验证与地氯雷他定治疗慢性荨麻疹疗效相关的多态性位点，为慢性荨麻疹临床个体化给药提供依据。