Genetic link between type 2 diabetes and atherosclerosis

描述(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，动脉粥样硬化患者经常患有2型糖尿病(T2 DM)。这两种疾病都有很强的遗传成分，并表现出家族聚集性。一个关键的悬而未决的问题是，常见的动脉粥样硬化和T2 DM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缺陷(APOE-/-)小鼠在喂食西方饮食时会患上T2 DM。相比之下，抗动脉粥样硬化的BALB/c(BALB)APOE-/-小鼠对它具有抵抗力。我们对B6Apoe-/-和BALB.Apoe-/-小鼠的杂交后代进行了数量性状基因座(QTL)分析，发现与动脉粥样硬化相关的QTL与位于5号染色体中部的高血糖QTL重合。通过将含有BALB.Apoe-/-QTL的5号染色体区域导入B6Apoe-/-小鼠，将产生速度同源品系，并分析产生的同源品系对动脉粥样硬化和T2 DM发生的遗传效应。将构建亚基因菌株，以确定动脉粥样硬化和高血糖是由相同的致病基因控制，还是由该区域两个相连但独特的基因控制。在目标2中，我们将进行功能研究，以测试HNF1A作为5号染色体QTL的候选基因。在人类中，HNF1a基因座的多态与冠心病和T2 DM风险相关。在B6和BALB之间的HNF1A基因中存在多个SNP，其中一个SNP位于外显子9，导致氨基酸替换。最近的全基因组关联研究已经确定了与细胞发育和功能有关的新的基因座，强调了胰岛素分泌在人类2型糖尿病发展中的作用。ApoE-/-小鼠表现出显著的细胞功能缺陷，但没有明显的胰岛素敏感性缺陷。当这些动物发生T2 DM时，观察到显著的巨噬细胞在胰岛中的渗透。在目标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可以预防糖尿病和改善B6ApoE-/-小鼠的动脉粥样硬化。总而言之，这项工作将揭示这两种重要疾病之间的基因联系。

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.