冠心病是人类最主要的死亡危险因素。我们和他人研究表明，三碘甲腺原氨酸（T3）是独立预测冠心病患者死亡风险的代谢物。目前其个体差异的原因尚不清楚。疾病状态下，DNA甲基化发生改变，可影响T3水平，而T3水平与代谢酶和转运体（ADME）密切相关，因此我们提出假说：在冠心病疾病状态下，ADME基因甲基化变异可导致T3水平过低，增加死亡风险。为了阐明此假设，我们前期用EWAS筛选出85个与T3有关联的ADME基因甲基化位点。本研究拟进一步，①基于Padlock探针测序检测85个甲基化位点，明确其与冠心病患者T3水平的关联性，并用孟德尔随机化分析揭示其因果关系；②明确其对死亡的风险，并构建生存预后模型；③用人肝微粒体代谢模型和细胞模型，从功能上明确DIO2等关键代谢酶基因甲基化对T3代谢的影响，阐明其甲基化对转录的调节作用。研究结果有助于阐明T3个体差异的表观遗传机制和提高对冠心病死亡风险的预测性。

Coronary artery disease (CAD) is one of the most common reason for human mortality. Reported literatures and our studies indicated that 3,5,3'-triiodothyronine (T3) is an independent marker for predicting death risks of CAD patients. To date, the mechanism for the individual difference of T3 level in CAD patients remains unclear. In a state of illness, DNA methylation variations occur and could affect T3 level, which is known to be closely related to and regulated by metabolic enzymes and transporters (ADME). We therefore hypothesis that in CAD states, variations of ADME gene methylation could cause an excessive reduction of T3 level and therefor increase the death risk for patients. To clarify this hypothesis, we used epigenome-wide association study (EWAS) for 112 CHD patients to screen out 85 ADME gene methylation sites suggestively associated with plasma T3 level. In the proposal, ① a targeted bisulfite sequencing based on Padlock probe will be applied to detect the methylation level of 85 ADME gene CpG loci and verify their association with plasma T3 level in 1,600 CHD patients and a Mendelian randomization method will then be applied to reveal the potential causal impact of methylation on the T3 level; ②we will clarify the predictive value for low T3 level increasing the risks of major adverse cardiovascular events and construct a risk prediction model. ③we will further verify the impact of DNA methylations of metabolic enzyme genes, such as DIO2, on T3 metabolism and explore the regulatory mechanism on transcription of key metabolic enzyme genes.The results of this study will give us a novel insight into the epigenetic mechanism on the inter-individual difference of T3 in CAD patients and will help improve predictive ability of mortality risk of CAD.