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: 8695343
• 负责人: WEIBIN SHI
• 金额: $ 34.37万
• 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/8695343
• 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（由适用提供）：与非糖尿病患者相比，糖尿病患者患动脉粥样硬化及其并发症的风险增加，而患有动脉粥样硬化的个体经常患有2型糖尿病（T2DM）。两种疾病都有很强的遗传成分并显示家庭聚类。一个关键的未解决的问题是，动脉粥样硬化和T2DM的常见形式之间是否存在遗传联系？我们发现，喂食西方饮食时，在C57BL/6（B6）背景上载载脂蛋白E缺陷型（APOE - / - ）小鼠。相反，动脉粥样硬化 - 抗性BALB/C（BALB）APOE - / - 小鼠对其具有抗性。我们对衍生自B6.apoe - / - 和Balb.apoe - / - 小鼠的间ross进行了定量性状基因座（QTL）分析，发现动脉粥样硬化的QTL与QTL相吻合的QTL恰好是高血糖的QTL，在5号铬粒的中部，在AIM 1的中部，我们将通过对AIM 1进行绘制，通过与该区域进行绘画，我们将在AIM 1中进行绘制。将通过引入将QTL的5号染色体区域引入BALB.APOE - / - 中的B6.APOE-/ - 小鼠来产生速度 - 综合线，并将分析所得的恒星菌株，以分析对动脉粥样硬化和T2DM发育的遗传作用。将构建亚综合菌株，以确定动脉粥样硬化和高血糖是否受到该地区相同的因果基因或两个连接但独特的基因的控制。在AIM 2中，我们将进行功能研究，以测试HNF1A作为5染色体QTL的承诺候选基因。 HNF1A基因座中的多态性与人类的冠状动脉疾病和T2DM风险有关。 B6和BALB之间的HNF1A基因内有多个SNP，在外显子9中具有一个SNP，导致氨基酸取代。最近的全基因组关联研究已经确定了在细胞开发和功能中实施的新局部研究，突出了人类T2DM开发中的胰岛素分泌。 B6.APOE - / - 小鼠在细胞功能中暴露了明显的缺陷，但在胰岛素敏感性方面没有明显的缺陷。当这些动物发生T2DM时，已经观察到胰岛中明显的巨噬细胞浸润。在AIM 3中，我们将使用这种独特的模型来研究胰岛注射的抑制是否会预防糖尿病和改善B6.APOE - / - 小鼠中的动脉粥样硬化。综上所述，这项工作将发现两种重要疾病之间的遗传联系。