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 与非糖尿病个体和患有动脉粥样硬化的个体相比，并发症频繁发生 患有 2 型糖尿病 (T2DM)。尽管遗传因素已被充分证明是主要因素 2 型糖尿病患者心血管事件的决定因素，因果变异的识别已 受到环境和遗传异质性的困扰。我们观察到 Apoe-/- 小鼠是动脉粥样硬化研究中常用的模型，其某些遗传因素会导致 T2DM 长期接触西方饮食后出现背景，但转移后产生耐药性 在某些其他背景上。对动脉粥样硬化具有抵抗力的 Apoe-/- 菌株具有显着的 与易感人群相比，非空腹血糖水平较低，并且葡萄糖耐量较高 到动脉粥样硬化。在源自 C57BL/6 (B6) 和 BALB/c (BALB) Apoe-/- 小鼠的杂交中，我们 鉴定出一个与动脉粥样硬化有关的重要 QTL，名为 Ath42，它与 Bglu13（Bglu13）精确重合。 血糖主要QTL。具有 BALB 供体片段的同类菌株，其中包含 Bglu13 和 B6-Apoe-/- 背景中的 Ath42 显示动脉粥样硬化病变大小显着减小， 血浆葡萄糖水平。因此，要检验的假设是糖尿病加速动脉粥样硬化 部分原因是影响这两种疾病的基因变异。为了检验这个假设，具体目标 1 将通过精细定位剖析含有 Bglu13 和 Ath42 的同源区域，以确定是否 动脉粥样硬化和血糖由相同或不同的致病基因控制。餐后 血糖水平（而非空腹血糖）与 2 型糖尿病患者发生心肌梗死有关 患者。餐后血糖升高通常伴随着餐后血糖升高。 低密度脂蛋白胆固醇和甘油三酯水平，加速动脉粥样硬化。在目标 2 中，我们将 表征从表型不同的 Apoe-/- 菌株中分离的 F2 群体以进行分区 餐后血糖与餐后血脂对动脉粥样硬化病变大小的个体影响 并确定将它们联系起来的遗传因素。餐后血糖水平也升高 伴有餐后炎症升高。我们观察到显着的巨噬细胞 喂食西方饮食的 Apoe-/- 小鼠胰岛中的浸润。在目标 3 中，我们将使用 F2 群体来 确定影响巨噬细胞浸润胰岛以及餐后的遗传因素 炎症。拟议的研究将导致识别连接两个的遗传因素 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.