Characterization of Atherosclerosis Modifier Genes

描述(申请人提供)：动脉粥样硬化性冠状动脉疾病是美国最常见的死亡原因。小鼠动脉粥样硬化模型有助于研究动脉粥样硬化的发病机制，并通过检测候选基因的低表达或过表达来鉴定动脉粥样硬化修饰基因。此外，无偏见的遗传方法已经被用来定位改变动脉粥样硬化易感性的小鼠基因的位置；现在，已经有报道成功地识别了其中的几个基因。通过品系杂交，我们分别确定了雌性和雄性小鼠中含有动脉粥样硬化易感性基因的Ath24和Ath26基因。通过使用来自菌株交叉队列的巨噬细胞的基因表达谱，我们找到了与特定转录本水平相关的遗传位点；并确定了其表达与动脉粥样硬化最相关的基因。值得注意的是，每个性别中最相关的基因都映射到了与该性别对应的Ath基因座。我们建议确认Ath24和Ath26基因的身份，并进行研究以深入了解它们的作用机制。我们还建议看看这些基因的人类同源基因中的遗传变异是否与冠状动脉疾病(CAD)有关。我们提供了初步的数据，人类在前24和26候选基因中的遗传变异实际上与冠心病有关。 公共卫生相关性：动脉粥样硬化性冠状动脉疾病(CAD)是美国最常见的死亡原因。这项拟议的研究可能会确定人类基因和途径，这些基因和途径以前没有被认为在动脉粥样硬化中发挥作用。这些可能导致诊断工具、新的药物靶点和治疗方法来预防或治疗冠心病。因此，拟议的研究解决了一个重大的健康问题，并为风险评估和预防的新模式带来了希望。

DESCRIPTION (provided by applicant): Atherosclerotic coronary disease is the most common cause of mortality in the United States. Mouse models of atherosclerosis have been useful for studying the pathogenesis of atherosclerosis and for the identification of atherosclerosis modifier genes by testing candidate genes through their under or over expression. Additionally, unbiased genetic methods have been used to map the loci of mouse genes that alter atherosclerosis susceptibility; and, the successful identification of a couple of these genes has now been reported. By the use of a strain intercross, we identified the Ath24 and Ath26 loci, which contain genes modifying atherosclerosis susceptibility in female and male mice, respectively. Through the use of gene expression profiling in macrophages derived from the strain intercross cohort, we found genetic loci that are associated with the levels of specific transcripts; and, we identified the genes whose expression was best correlated with atherosclerosis. Remarkably, the best correlated gene in each sex mapped to the corresponding Ath locus for that sex. We propose to confirm the identity of the Ath24 and Ath26 genes, and perform studies to gain insight into their mechanism of action. We also propose to see if genetic variation in the human orthologs of these genes is associated with coronary artery disease (CAD). We present preliminary data that human genetic variation in the top Ath24 and Ath26 gene candidates are in fact associated with CAD. PUBLIC HEALTH RELEVANCE: Atherosclerotic coronary disease (CAD) is the most common cause of mortality in the United States. The proposed studies may identify human genes and pathways not previously recognized to play a role in atherosclerosis. These may lead to diagnostic tools, novel drug targets, and therapies to prevent or treat CAD. Thus, the proposed studies address a significant health concern and offer hope for new modes of risk assessment and prevention.