Genetic connections between type 2 diabetes and atherosclerosis

摘要 糖尿病患者患动脉粥样硬化性血管疾病的风险增加2~4倍 并发症与非糖尿病患者和动脉粥样硬化患者的比较 患有2型糖尿病(T2 DM)。尽管遗传因素已经被充分记录为主要的 2型糖尿病患者心血管事件的决定因素，因果变量的识别 被环境和遗传的异质性搞混了。我们观察到APOE-/- 小鼠是动脉粥样硬化研究的常用模型，其发病机制与某些基因有关 长期接触西方饮食但在转移后产生抵抗力的背景 在某些其他背景下。抗动脉粥样硬化的APOE-/-菌株具有显著的 非空腹血糖水平较低，表现出比易感人群更高的葡萄糖耐量 致动脉粥样硬化。在C57BL/6(B6)和BALB/c(BALB)APOE-/-小鼠的杂交中，我们 发现了一个与动脉粥样硬化相关的重要QTL，命名为Ath42，它恰好与Blu13，a 控制血糖的主效QTL。一株带有BALB供体片段的同源菌株，该片段含有Blu13和 在B6-APOE-/-背景中的Ath42显示动脉粥样硬化病变大小和 血糖水平。因此，需要检验的假设是糖尿病患者动脉粥样硬化加速。 在一定程度上是由于影响这两种疾病的基因变异。为了检验这一假设，具体目标1 将通过精细作图来解剖含有Blu13和Ath42的同源区域，以确定 动脉粥样硬化和血糖由相同或不同的因果基因控制(S)。餐后 2型糖尿病患者发生心肌梗死与血糖水平有关，而与空腹血糖无关 病人。餐后血糖水平升高常常伴随餐后血糖升高 低密度脂蛋白胆固醇和甘油三酯的水平，这会加速动脉粥样硬化。在目标2中，我们将 从表型分化的APOE-/-菌株中分离F2群体的特征 餐后血糖与餐后血脂对动脉粥样硬化病变大小的个体贡献 并找出连接它们的遗传因素。餐后血糖水平升高也是 伴有严重的餐后炎症。我们观察到显著的巨噬细胞 用西方饮食喂养的APOE-/-小鼠胰岛中的渗透。在目标3中，我们将使用F2种群来 确定影响巨噬细胞向胰岛和餐后渗透的遗传因素 发炎。这项拟议中的研究将导致识别将两者联系在一起的遗传因素 重要疾病，揭示心血管并发症防治新靶点 在糖尿病患者中。

Abstract Diabetic patients have 2~4-fold increased risk of developing atherosclerotic vascular disease and its complications compared to non-diabetic individuals, and individuals with atherosclerosis frequently have type 2 diabetes mellitus (T2DM). Although genetic factors have been well documented as a major determinant of cardiovascular events in type 2 diabetic patients, identification of causal variants has been confounded by both environmental and genetic heterogeneity. We have observed that Apoe-/- mice, a commonly used model for atherosclerosis research, develop T2DM on certain genetic backgrounds after prolonged exposure to a Western diet but become resistant after being transferred on certain other backgrounds. The Apoe-/- strains that are resistant to atherosclerosis have significantly lower non-fasting glucose levels and display greater glucose tolerance than those that are susceptible to atherosclerosis. In an intercross derived from C57BL/6 (B6) and BALB/c (BALB) Apoe-/- mice, we identified a significant QTL for atherosclerosis, named Ath42, which coincides precisely with Bglu13, a major QTL for blood glucose. A congenic strain with a BALB donor segment harboring Bglu13 and Ath42 in the B6-Apoe-/- background showed significant reductions in atherosclerotic lesion size and plasma glucose level. Thus, the hypothesis to be tested is that accelerated atherosclerosis in diabetes is due, in part, to genetic variants that influence both disorders. To test this hypothesis, specific aim 1 will dissect the congenic region harboring Bglu13 and Ath42 through fine mapping to determine whether atherosclerosis and blood glucose are controlled by the same or different causal gene(s). Postprandial glucose levels, rather than fasting glucose, are related to incident myocardial infarction in type 2 diabetic patients. Elevated postprandial glucose levels are frequently accompanied by elevated postprandial levels of LDL cholesterol and triglyceride, which accelerate atherosclerosis. In aim 2, we will characterize a segregating F2 population from phenotypically divergent Apoe-/- strains to partition individual contribution of postprandial glucose versus postprandial lipids to atherosclerotic lesion sizes and identify genetic factors that connect them. Elevated postprandial glucose levels are also accompanied by elevated postprandial inflammation. We have observed significant macrophage infiltration in the islets of Apoe-/- mice fed a Western diet. In aim 3, we will use the F2 population to identify genetic factors affecting macrophage infiltration into the islets as well as postprandial inflammation. The proposed research will lead to identification of genetic factors that connect two important diseases and reveal new targets for prevention and treatment of cardiovascular complications in diabetic patients.