Integrative genetic approaches to Atherosclerosis

常见的人类疾病是由许多基因和环境的相互作用造成的。在过去的几年中，全基因组关联研究（GWAS）已经成功地确定了许多新的基因座潜在的心血管疾病的特点。然而，这些基因通常是在背景下识别的，在大多数情况下，即使在非常大的研究中，也只识别了一小部分遗传成分。 我们的实验室正在采用系统遗传学方法来了解复杂疾病中的高阶相互作用。这涉及DNA变异、全局基因表达和临床表型的整合。在系统遗传学中，转录水平被视为遗传变异的函数，而不仅仅是病例与对照。 我们建议应用这种系统遗传学方法，试图更好地了解人类染色体9 p21单倍型和冠状动脉疾病易感性之间的关联。在目的1中，我们提出了在人类细胞和小鼠遗传杂交中的组织培养中的9 p21区域中的基因的表达模式的特征。在目标2中，我们详细分析了易感等位基因对RNA剪接的影响，并研究了该位点编码能够调节基因表达的microRNA的可能性。在目标3中，我们利用一系列转基因/敲除模型来测试基因在基因座上的作用，并验证目标1和2的发现。

Common human diseases result from the interplay of many genes and the environment. During the past few years, genome-wide association studies (GWAS) have succeeded in identifying many novel loci underlying cardiovascular disease traits. However, the genes are generally identified out of context and, in most cases, a very small fraction of the genetic component has been identified, even in very large studies. Our laboratory is employing a systems genetic approach to understand the higher order interactions in complex diseases. This involves the integration of DNA variation, global gene expression, and clinical phenotypes. In systems genetics, transcript levels are examined as a function of genetic variation, not simply in cases versus controls. We propose to apply this systems genetics approach to attempt to better understand the association between a haplotype on human chromosome 9p21 and coronary artery disease susceptibility. In Aim 1, we propose to characterize the patterns of expression of the genes in the 9p21 region in tissue culture in human cells and in mouse genetic crosses. In Aim 2, we analyze in detail the effects of the susceptibility alleles on RNA splicing and we examine the possibility the locus encodes microRNAs capable of regulating gene expression. In Aim 3 we utilize a series of transgenic/knockout models to test the role of genes at the locus and to validate findings from Aims 1 and 2.