Genetic link 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

• 批准号: 8584827
• 负责人: WEIBIN SHI
• 金额: $ 33.46万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-05 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8584827
• 关键词: Accounting; Affect; Albumins; Amino Acid Substitution; Animals; Apolipoprotein E; Arterial Fatty Streak; Atherosclerosis; Bioinformatics; Blood Glucose; Breeding; Candidate Disease Gene; Cell physiology; Cells; Cessation of life; Chromosomes, Human, Pair 5; Complex; Congenic Mice; Congenic Strain; Coronary heart disease; Defect; Development; Diabetes Mellitus; Diet; Disease; Exhibits; Exons; Fasting; Genes; Genetic; Genetic Engineering; Genetic Polymorphism; Genetic Variation; Genomics; Genotype; Glucose; Human; Hyperglycemia; Inbred BALB C Mice; Individual; Infiltration; Inflammation; Insulin; Insulin Resistance; Knockout Mice; Lead; Link; Liver; Maps; Metabolic Diseases; Metabolic syndrome; Modeling; Mus; Myocardial Infarction; N.I.H. Research Support; Names; Non-Insulin-Dependent Diabetes Mellitus; Pancreas; Pathologic Processes; Pathway interactions; Peripheral arterial disease; Phase; Phenotype; Prevention strategy; Production; Proteins; Quantitative Trait Loci; Rattus; Research Design; Resistance; Risk; Role; Speed; Stroke; Testing; Therapeutic Intervention; Transgenic Mice; United States; Validation; Work; blood glucose regulation; congenic; cytokine; diabetes risk; diabetic; diabetic patient; feeding; genetic analysis; genetic variant; genome wide association study; glucose metabolism; human RCN2 protein; insulin secretion; insulin sensitivity; islet; macrophage; mouse model; mutant; non-diabetic; novel; oxidized lipid; prevent; promoter; public health relevance; response; therapeutic development; three dimensional structure; tool; trait; treatment strategy

DESCRIPTION (provided by applicant): Diabetic patients have an increased risk of developing atherosclerosis and its complications compared with non-diabetic individuals, and individuals with atherosclerosis frequently have type 2 diabetes mellitus (T2DM). Both diseases have a strong genetic component and show familial clustering. A critical unsolved question is whether there are genetic connections between common forms of atherosclerosis and T2DM? We have found that apolipoprotein E-deficient (Apoe-/-) mice on the C57BL/6 (B6) background develop T2DM when fed a Western diet. In contrast, atherosclerosis- resistant BALB/c (BALB) Apoe-/- mice are resistant to it. We performed quantitative trait locus (QTL) analysis on an intercross derived from B6.Apoe-/- and BALB.Apoe-/- mice and found that the QTL for atherosclerosis coincided with the QTL for hyperglycemia in the middle portion of chromosome 5. In Aim 1, we will conduct fine mapping for this region by making congenic strains. Speed-congenic lines will be generated by introducing the chromosome 5 region harboring the QTLs from BALB.Apoe-/- into B6.Apoe-/- mice, and the resultant congenic strains will be analyzed for genetic effects on atherosclerosis and T2DM development. Subcongenic strains will be constructed to determine whether atherosclerosis and hyperglycemia are controlled by the same causal gene or two linked but unique genes in the region. In Aim 2, we will conduct functional study to test Hnf1a as a promising candidate gene for the chromosome 5 QTLs. Polymorphisms in the Hnf1a locus are associated with coronary heart disease and T2DM risk in humans. There are multiple SNPs within the Hnf1a gene between B6 and BALB with one SNP in exon 9 leading to amino acid substitution. Recent genome- wide association studies have identified new loci that are implicated in ¿-cell development and function, highlighting insulin secretion in the development of T2DM in humans. B6.Apoe-/- mice exhibit significant defects in ¿ cell function but have no significant defects in insulin sensitivity. Significant macrophage infiltration in the islets has been observed when T2DM occurs in these animals. In Aim 3, we will use this unique model to investigate whether inhibition of islet inflammation would prevent diabetes and ameliorate atherosclerosis in B6.Apoe-/- mice. Taken together, this work will uncover genetic connections between the two important diseases.

描述（由申请人提供）：与非糖尿病患者相比，糖尿病患者发生动脉粥样硬化及其并发症的风险增加，动脉粥样硬化患者通常患有2型糖尿病（T2DM）。这两种疾病都有很强的遗传成分，并表现出家族聚集性。一个关键的未解决的问题是，常见形式的动脉粥样硬化和2型糖尿病之间是否存在遗传联系？我们发现C57BL/6 （B6）背景的载脂蛋白e缺乏（Apoe-/-）小鼠在喂食西方饮食时发生T2DM。相反，抗动脉粥样硬化的BALB/c (BALB) Apoe-/-小鼠对它有抗性。我们对B6的一个杂交进行了数量性状位点（QTL）分析。Apoe-/-和BALB。Apoe-/-小鼠，发现动脉粥样硬化QTL与5号染色体中间部分的高血糖QTL一致。在Aim 1中，我们将通过制作同源菌株对该区域进行精细作图。通过引入含有BALB qtl的5号染色体区域，可以获得快速同源系。Apoe-/-转化成B6。Apoe-/-小鼠和由此产生的同源菌株将被分析遗传对动脉粥样硬化和T2DM发展的影响。将构建亚同源菌株以确定动脉粥样硬化和高血糖是由同一致病基因控制还是由该地区两个相互关联但独特的基因控制。在Aim 2中，我们将进行功能研究，以测试Hnf1a作为5号染色体qtl的有希望的候选基因。Hnf1a基因座的多态性与人类冠心病和2型糖尿病风险相关。在Hnf1a基因B6和BALB之间存在多个SNP，其中一个SNP位于外显子9，导致氨基酸替代。最近的全基因组关联研究发现了与细胞发育和功能有关的新基因座，强调了胰岛素分泌在人类T2DM发展中的作用。B6。Apoe-/-小鼠表现出明显的细胞功能缺陷，但胰岛素敏感性无明显缺陷。当这些动物发生T2DM时，观察到胰岛有明显的巨噬细胞浸润。在Aim 3中，我们将使用这个独特的模型来研究抑制胰岛炎症是否会预防糖尿病和改善B6动脉粥样硬化。Apoe - / -小鼠。总的来说，这项工作将揭示这两种重要疾病之间的遗传联系。