Genetic link between type 2 diabetes and atherosclerosis

描述（申请人提供）：与非糖尿病个体相比，糖尿病患者发生动脉粥样硬化及其并发症的风险增加，患有动脉粥样硬化的个体经常患有2型糖尿病（T2 DM）。这两种疾病都有很强的遗传成分，并显示出家族聚集性。一个关键的未解决的问题是是否有常见形式的动脉粥样硬化和T2 DM之间的遗传联系？我们发现，C57 BL/6（B6）背景的载脂蛋白E缺陷（Apoe-/-）小鼠在喂食西方饮食时发生T2 DM。我们对B6.Apoe-/-和BALB.Apoe-/-小鼠的互交后代进行了数量性状基因座（QTL）分析，发现动脉粥样硬化的QTL和高血糖的QTL位于第5染色体的中部。在目标1中，我们将通过制备同源菌株对该区域进行精细定位。将通过将携带来自BALB.Apoe-/-的QTL的染色体5区域引入B6. Apoe-/-小鼠中来产生速度同源系，并分析所得同源系对动脉粥样硬化和T2 DM发展的遗传效应。将构建亚同源菌株以确定动脉粥样硬化和高血糖症是否由同一致病基因或该区域中两个连锁但独特的基因控制。目的二是进行功能研究，验证Hnf 1a作为5号染色体QTL候选基因的可行性。Hnf 1a基因座多态性与人类冠心病和T2 DM风险相关B6和BALB之间Hnf 1a基因存在多个SNP，其中第9外显子的一个SNP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基因座，突出了人类2型糖尿病发展中的胰岛素分泌。B6.Apoe-/-小鼠在细胞功能方面表现出显著缺陷，但在胰岛素敏感性方面没有显著缺陷。当这些动物发生T2 DM时，在胰岛中观察到显著的巨噬细胞浸润。在目标3中，我们将使用这种独特的模型来研究抑制胰岛炎症是否会预防糖尿病并改善B6.Apoe-/-小鼠的动脉粥样硬化。总之，这项工作将揭示这两种重要疾病之间的遗传联系。

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.