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已被用于研究动脉粥样硬化的发病机制，并用于通过检测候选基因的过表达或低表达来鉴定动脉粥样硬化修饰基因。此外，无偏遗传学方法已被用于绘制改变动脉粥样硬化易感性的小鼠基因的位点;并且，现在已经报道了这些基因中的一对的成功鉴定。通过使用一个菌株互交，我们确定了Ath 24和Ath 26位点，其中包含的基因修改动脉粥样硬化的易感性，在女性和男性小鼠，分别。通过使用来自菌株交叉队列的巨噬细胞中的基因表达谱，我们发现了与特定转录物水平相关的遗传位点;并且，我们鉴定了其表达与动脉粥样硬化最相关的基因。值得注意的是，每个性别中最好的相关基因映射到该性别的相应Ath位点。我们建议确认Ath 24和Ath 26基因的身份，并进行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直系同源基因的遗传变异是否与冠状动脉疾病（CAD）有关。我们目前的初步数据表明，人类遗传变异的前Ath 24和Ath 26基因候选人实际上与CAD。

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.