Characterization of Atherosclerosis Modifier Genes

描述（由申请人提供）：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对于研究动脉粥样硬化的发病机制和通过检测候选基因的过表达或过表达来鉴定动脉粥样硬化修饰基因是有用的。此外，无偏遗传方法已被用于绘制改变动脉粥样硬化易感性的小鼠基因位点；现在已经有报道成功地鉴定了其中的几个基因。通过品系交叉，我们分别鉴定了Ath24和Ath26位点，这两个位点分别包含了雌性和雄性小鼠动脉粥样硬化易感性的基因。通过使用来自菌株交叉队列的巨噬细胞的基因表达谱，我们发现了与特定转录物水平相关的遗传位点；同时，我们确定了与动脉粥样硬化最相关的基因。值得注意的是，每个性别中相关性最好的基因都与该性别对应的Ath位点相对应。我们建议确认Ath24和Ath26基因的身份，并开展研究以深入了解其作用机制。我们还建议看看这些基因的人类同源基因的遗传变异是否与冠状动脉疾病（CAD）有关。我们提供的初步数据表明，Ath24和Ath26候选基因的人类遗传变异实际上与CAD有关。

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.