Genetic connections between type 2 diabetes and atherosclerosis

2 型糖尿病与动脉粥样硬化之间的遗传联系

基本信息

批准号：
10319991
负责人：
WEIBIN SHI
金额：
$ 39.89万
依托单位：
UNIVERSITY OF VIRGINIA
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-01-10 至 2024-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10319991
关键词：
Adipose tissue Affect Apolipoprotein E Arterial Fatty Streak Atherosclerosis Attention Blood Glucose Blood Vessels Candidate Disease Gene Cardiovascular system Cessation of life Cholesterol Complex Complications of Diabetes Mellitus Confidence Intervals Congenic Strain Consumption Coronary heart disease Country Development Diabetes Mellitus Disease Environmental Risk Factor Event Exposure to Flow Cytometry Gene Expression Profiling Genes Genetic Genetic Heterogeneity Genetically Engineered Mouse Glucose Glucose Intolerance Growth High Fat Diet Human Human Genome Inbred BALB C Mice Inbred Strain Individual Infiltration Inflammation Inflammatory LDL Cholesterol Lipoproteins Lipids Liver Metabolic Diseases Modeling Mus Myocardial Infarction Names Non-Insulin-Dependent Diabetes Mellitus Pathogenicity Pathway interactions Peripheral arterial disease Persons Phase Phenotype Plasma Population Predisposition Prevention Process Quantitative Trait Loci Research Resistance Risk Role Skeletal Muscle Stroke Testing Tissues Triglycerides Type 2 diabetic United States Work bioinformatics tool causal variant congenic diabetic diabetic patient fasting glucose genetic analysis genetic linkage analysis genetic variant genome wide association study genomic tools glucose metabolism glucose tolerance impaired glucose tolerance interest islet low density lipoprotein triglyceride macrophage mortality mouse model non-diabetic novel strategies prevent recruit resistant strain tool trait western diet

项目摘要

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.

抽象的糖尿病患者患动脉粥样硬化血管疾病及其的风险增加了2至4倍与非糖尿病患者和动脉粥样硬化的个体相比，并发症经常患有2型糖尿病（T2DM）。尽管遗传因素已被充分记录为主要在2型糖尿病患者中的心血管事件的决定因素，因果变异的鉴定具有被环境和遗传异质性混淆。我们观察到apoe - / - 小鼠是一种用于动脉粥样硬化研究的常用模型，在某些遗传上发展了T2DM 长时间接触西方饮食后的背景在某些其他背景。抗动脉粥样硬化的APOE - / - 菌株显着比易感性的葡萄糖水平较低，并且显示出更大的葡萄糖耐受性动脉粥样硬化。在源自C57BL/6（B6）和BALB/C（BALB）APOE - / - 鼠标的间交叉中，我们鉴定出一个具有ATH42的动脉粥样硬化的显着QTL，它与BGLU13完全重合血糖的主要QTL。带有BGLU13和BALB捐赠者细分市场的先天性压力 B6-apoe - / - 背景中的ATH42显示动脉粥样硬化病变的大小和血浆葡萄糖水平。因此，要检验的假设是糖尿病的动脉粥样硬化加速部分归因于影响这两种疾病的遗传变异。为了检验这一假设，具体目标1 将通过精细映射剖析藏有BGLU13和ATH42的先天区域，以确定是否是否动脉粥样硬化和血糖由相同或不同的因果基因控制。餐后葡萄糖水平而不是禁食葡萄糖与2型糖尿病的发生心肌梗塞有关患者。餐后葡萄糖水平升高，经常伴有餐后升高 LDL胆固醇和甘油三酸酯的水平，加速动脉粥样硬化。在AIM 2中，我们将表征从表型发散的apoe - / - 菌株到分配的分离的F2种群餐后葡萄糖与餐后脂质对动脉粥样硬化病变大小的个人贡献并确定连接它们的遗传因素。餐后葡萄糖水平也升高伴随着餐后炎症升高。我们已经观察到明显的巨噬细胞喂食西方饮食的Apoe - / - 小鼠的胰岛浸润。在AIM 3中，我们将使用F2人群确定影响巨噬细胞浸润到胰岛的遗传因素以及餐后炎。拟议的研究将导致鉴定连接两个的遗传因素重要疾病并揭示了预防和治疗心血管并发症的新目标在糖尿病患者中。