新近研究发现NEK7可激活NLRP3炎症小体，并促进下游细胞因子的释放，可能是促使斑块不稳定/破裂进而发生冠心病不良心血管事件(MACEs)的始动因子。我们前期研究亦发现，炎症小体活化通路下游基因IL-1B多态性和冠心病MACEs的发生有关，并且突变可以带来转录活性的增加。然而，因各种潜在混杂因素的干扰我们尚无法推断细胞因子表型与MACE的关联。因此本研究结合国际流行的孟德尔随机化法，采用队列随访设计，以基因型为工具变量，通过构建基因型-表型，基因型-MACEs的关联来推断NEK7/NLRP3炎症小体活化通路细胞因子表型与MACEs发生的关联，同时绘制有向非循环图（DAG）获得潜在混杂因素的调整模型，使用细胞学实验和模式动物验证遗传变异对斑块稳定性的影响。本研究可进一步阐明动脉粥样斑块不稳定的分子生物学机制，并为预测冠心病病例发生MACEs提供新的分子标志物，促进冠心病精准医学的实践。

The major adverse cardiac events (MACEs) are the direct and/or indirectly causes of the death in the coronary heart disease (CAD) patients, of which about 1/4 of the deaths could be avoided. The recent studies revealed that NEK7 kinases could activate the NLRP3 inflammasome and then initiated the downstream cytokines to release, which were the important reasons for the instability of plaque rupture and thrombosis. Our previous study have found that, the genetic variants in Interleukin-1 B (IL-1B) gene, which encode the IL-1 downstream cytokines in the inflammasome activation pathway, are associated with MACEs and the increasing transcriptional activity of IL-1B. However, due to the interference of various potential confounding factors, we could not infer the relationships between cytokine phenotype and MACEs. Therefore, in this study, we will combine the latest epidemiological method - Mendelian randomization method and the cohort follow-up study design, with genotypes as instrumental variables, by constructing the relationships between genotypes and phenotypes, genotypes and MACEs outcomes, to infer the relationships between the relative cytokine phenotypes(NEK7, NLRP3, Caspase-1 and IL-1/18) and MACEs outcomes. And also, we have drawn a directed acyclic graph (DAG) to obtain a minimal sufficient adjustment set of variables (MSAS), which is used to adjust the potential confounding factors. Besides, we will test the effects on the stability of plaque of the genetic variations, using the cytological experiments and ApoE(-/-) gene knockdown animal model. This study will further elucidate the molecular biology mechanism of atherosclerotic plaque instability, provide new molecular biomarkers for the prediction of MACEs in coronary heart disease patients and promote the practice of CAD precision medicine.