Cloning QTL Genes for Plasma HDL Cholesterol

描述(申请人提供)：心脏病仍然是工业化社会的主要死亡原因，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它的发病率。进一步治疗进展的主要途径是学习如何提高高密度脂蛋白，这是预防心脏病的一种主要保护措施；据估计，高密度脂蛋白适度增加可能会导致心脏病发病率的大幅下降。小鼠是寻找高密度脂蛋白基因及其编码的蛋白质的极佳模型。不仅在小鼠和人类中发现的高密度脂蛋白的数量性状基因座(QTL)位于一致的位置，而且小鼠模型可以用来确定提高高密度脂蛋白水平的多态性是否也降低了动脉粥样硬化的风险。我们相信，通过识别所有(或几乎所有)导致一个复杂特征的基因，我们将学到很多东西。我们认为，高密度脂蛋白是这项研究的最佳复杂性状，因为高密度脂蛋白在小鼠身上的QTL研究，在人类中的连锁和全基因组关联研究，以及对高密度脂蛋白新陈代谢的大量知识。对这一复杂特征的任何洞察都将与我们思考导致许多重大疾病的其他复杂特征的方式有相当大的相关性。在这一赠款期间，目标1将是使用遗传和生物信息学工具的组合来识别另外7个影响高密度脂蛋白的QTL基因，这些工具在过去几年中被证明是如此成功。当我们确定这些基因时，其中一些可能在高密度脂蛋白新陈代谢中具有已知的功能；然而，另一些可能是相当新的，它们调节高密度脂蛋白水平的机制可能完全未知。对于这些新的基因，重要的是我们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，我们建议通过进行转基因或敲除/敲除，通过其他功能研究，并通过在人类群体中测试这些基因(通过合作)来获得额外的证据。最后，在目标3中，我们建议研究QTL基因之间的相互作用以及它们如何相互作用形成网络。 与公共卫生相关：心脏病是工业化社会的主要死亡原因，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降低了心脏病的发病率。进一步治疗进展的主要途径是学习如何提高高密度脂蛋白，高密度脂蛋白提供预防心脏病的保护。这一建议试图确定导致高密度脂蛋白数量性状基因座的基因，其中一些可能是很好的药物靶点。

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.