遗传因素是痛风发病的主要因素，但已知的痛风易感基因多与尿酸代谢有关，不能解释大部分高尿酸血症患者不发生痛风这一现象。课题组前期在痛风大样本队列中（痛风4619 VS 对照7924）通过GWAS发现了一个全新的痛风易感基因KCNQ1，它编码钾离子通道蛋白，但与痛风间的关联未知。我们初步研究发现，KCNQ1调控单核细胞IL-1β的分泌，推测其可能通过影响单核细胞的功能，参与痛风发病。本项目拟对此进行研究：1）人体水平：收集含有KCNQ1 SNP的单核细胞，研究其对单核细胞功能的影响及可能的机制。2）动物水平：构建KCNQ1基因敲除小鼠和新型痛风气囊小鼠模型，整体状态下观察KCNQ1对痛风发病及单核细胞功能的影响。3）细胞水平：应用转基因技术，使KCNQ1基因在单核细胞（THP-1）内高表达或低表达，观察单核细胞功能变化及可能机制。本研究将揭示新的痛风发病机制，为痛风新药研发奠定基础。

Genetic factor is the main cause for gout. Previous studies have reported several risk-associated genes for gout which are mainly related to the metabolism of uric acid. The reason why almost hyperuricemia patients not take gout disease has not been known. We have defined a gout causal gene KCNQ1 which encodes a pore-forming subunit of the voltage-dependent K+ ion channel by GWAS (case 4619 VS 7924 control). However, the relationship between KCNQ1 and gout is still unknown. We found the excretion of IL-1β is regulated by KCNQ1 in monocytes. Thus we speculate KCNQ1 may affect monocyte function in gout pathogenesy. The study will be performed as follows: 1) human level: The effect of KCNQ1 rs179785 SNP on monocyte function will be studied. 2) animal level: The function of KCNQ1 in monocytes and gout will be studied in KCNQ1-/-mouse and air-pouch mouse model of gout. 3) cell level: Functional changes of monocyte cell line THP-1 will be observed when KCNQ1 gene is overexpressed or down-regulated by transgenetic technology. In this project, we will try to reveal new mechanisms of gout and provide new insights into the development of drugs for gout.