Cloning QTL Genes for Plasma HDL Cholesterol

描述（由申请人提供）：在工业化社会中，尽管生活方式的改变和降低低密度脂蛋白胆固醇的有效药物已经降低了心脏病的发病率，但心脏病仍然是导致死亡的主要原因。进一步治疗进展的主要途径在于学习如何提高HDL，这是预防心脏病的主要保护；据估计，HDL的适度增加可能会导致心脏病发病率的大幅下降。老鼠是寻找高密度脂蛋白基因和它们编码的蛋白质的绝佳模型。不仅在小鼠和人类中发现高密度脂蛋白的数量性状位点（qtl）在一致的位置，而且小鼠模型可用于确定提高高密度脂蛋白水平的多态性是否也降低动脉粥样硬化风险。我们相信，通过识别一个复杂特征背后的所有（或几乎所有）基因，我们将学到很多东西。我们认为高密度脂蛋白是最适合这项工作的复杂性状，因为在小鼠中有大量的高密度脂蛋白QTL研究，在人类中有大量的连锁和全基因组关联研究，以及对高密度脂蛋白代谢的大量了解。对这一复杂特征的任何见解都将与我们思考导致许多主要疾病的其他复杂特征的方式具有相当大的相关性。在此资助期间，目标1将是利用遗传和生物信息学工具的结合来确定影响HDL的另外7个QTL基因，这些工具在过去几年中已被证明是非常成功的。当我们确定这些基因时，其中一些可能在高密度脂蛋白代谢中具有已知的功能；然而，其他的可能是相当新的，它们调节HDL水平的机制可能是完全未知的。对于这些新基因，重要的是我们要用更多的证据来验证它们在高密度脂蛋白代谢中的作用。因此，在目标2中，我们建议通过转基因或敲除/敲除基因，通过其他功能研究，以及通过在人群中测试这些基因（通过合作）来获得额外的证据。最后，在Aim 3中，我们建议研究QTL基因的相互作用以及它们如何相互作用以形成网络。

DESCRIPTION (provided by applicant): Heart disease is still the major cause of death in industrialized societies even though lifestyle changes and effective drugs that lower LDL cholesterol have reduced its incidence. The major avenue to further therapeutic progress lies in learning how to raise HDL, a major protection against heart disease; it has been estimated that a modest increase in HDL could lead to a large decrease in heart disease incidence. The mouse is an excellent model for finding HDL genes and the proteins they encode. Not only are quantitative trait loci (QTLs) for HDL in mouse and human found in concordant locations, but the mouse model can be used to determine whether a polymorphism that raises HDL levels also reduces atherosclerosis risk. We believe that we would learn much by identifying all (or nearly all) of the genes underlying one complex trait. We suggest that HDL is the best complex trait for such an undertaking because of the substantial infrastructure of HDL QTL studies in the mouse, linkage and genome wide association studies in humans, and considerable knowledge about HDL metabolism. Any insights into this complex trait will have considerable relevance to the ways in which we think about other complex traits responsible for many of our major diseases. In this grant period, Aim 1 will be to identify 7 additional QTL genes that affect HDL using the combination of genetic and bioinformatic tools that have proven so successful during the last few years. When we identify these genes, some may have a known function in HDL metabolism; others, however, may be quite new, and the mechanisms by which they modulate HDL levels may be completely unknown. For these novel genes, it is important that we verify their role in HDL metabolism with additional evidence. Therefore in Aim 2 we propose to obtain that extra evidence by making transgenics or knockouts/knockins, by other functional studies, and by testing these genes in human populations (by collaboration). Finally in Aim 3, we propose to study the interactions of QTL genes and how they work with each other to form networks. PUBLIC HEALTH RELEVANCE: Heart disease is the major cause of death in industrialized societies even though lifestyle changes and effective drugs that lower LDL cholesterol have reduced its incidence. The major avenue to further therapeutic progress lies in learning how to raise HDL, which provides protection against heart disease. This proposal seeks to identify the genes causal for HDL quantitative trait loci; some of them may be good drug targets.