Cloning QTL Genes for Plasma HDL Cholesterol

描述(申请人提供)：动脉粥样硬化是缺血性心血管疾病(CVD)的病理基础，是工业化国家的主要死亡原因。有两条证据表明，高水平的血浆高密度脂蛋白胆固醇(HDLC)可以预防心血管疾病。首先，流行病学研究表明，高密度脂蛋白胆固醇水平与心血管疾病的发病率呈负相关。其次，提高血浆高密度脂蛋白胆固醇水平与减少小鼠、兔子和人类的动脉粥样硬化有关。由于血浆高密度脂蛋白-C水平在很大程度上是由遗传决定的，数量性状基因座(QTL)已被用来定位高密度脂蛋白调节染色体(Chr)基因座。比较小鼠和人类的高密度脂蛋白QTL，发现它们是一致的，因此，在小鼠中寻找隐藏在高密度脂蛋白-C QTL的基因可能揭示人类的高密度脂蛋白调节基因，这可能为治疗提供靶点。我们的长期目标是寻找调节血浆高密度脂蛋白胆固醇水平的新基因，为心血管疾病提供新的治疗靶点。在这一方案中，我们选择了基于以下标准来确定位于Chr1(Hdlq33)和Chr6(Hdlq12)上的一个高密度脂蛋白-C QTL的基因：1)至少发现了一个人类同源的高密度脂蛋白-C QTL；2)在多个杂交组合中发现了该QTL，和/或它们与电子高密度脂蛋白-C QTL中的QTL一致；3)该QTL可以从紧密连锁的QTL(S)中分离出来，因此我们知道哪些杂交组合检测到了我们要研究的QTL；4)这些杂交涉及到测序的菌株(B6、A、DBA/2和129)，因为这样更容易找到序列差异；5)可利用的遗传资源有：同源品系、共生品系、重组近交系。我们建议通过以下特定的目标来识别这两个QTL的基因。首先，我们将使用基因组、统计和生物信息学工具来缩小QTL。其次，我们将从基因上缩小QTL。第三，我们将根据候选基因的序列、表达和功能在小鼠身上进行测试，并在关联性研究中测试它们与人类心血管疾病的相关性。通过这笔赠款，我们将找到调节血液高密度脂蛋白胆固醇(即所谓的“好胆固醇”)水平的基因。作用于这些基因的药物可能会增加高密度脂蛋白胆固醇，降低心血管疾病的发生率。

DESCRIPTION (provided by applicant): Atherosclerosis is the pathological basis for ischemic cardiovascular disease (CVD), the leading cause of death in the industrialized nations. Two lines of evidence indicate that high levels of plasma high-density lipoprotein cholesterol (HDL-C) protect against CVD. First, epidemiological studies have shown an inverse relationship between HDL-C levels and the incidence of CVD. Second, raising plasma HDL-C levels is associated with reduced atherosclerosis in mice, rabbits and humans. Because plasma HDL-C levels are largely genetically determined, quantitative trait locus (QTL) mapping has been used to localize HDL-regulating chromosomal (Chr) loci. Comparison of mouse and human HDL QTLs revealed that they are concordant, therefore finding genes underlying HDL-C QTLs in mice may reveal HDL-regulating genes in humans, which may provide therapeutic targets. Our long-term objective is to find new genes regulating plasma HDL-C levels to provide new therapeutic targets for CVD. In this proposal, we have chosen to identify the genes for one HDL-C QTL on Chr 1 (Hdlq33) and one on Chr 6 (Hdlq12) based on the following criteria: 1) at least one human homologous HDL-C QTL has been found; 2) the QTL has been found in multiple crosses, and/or they coincide with in silico HDL-C QTLs; 3) the QTL can be separated from closely linked QTL(s) so we know which crosses have detected the QTL we want to study; 4) the crosses involve sequenced strains (B6, A, DBA/2 and 129) because sequence differences will then be easier to find; and 5) other genetic resources are available: congenic strains, consomic strains, recombinant inbred strains. We propose to identify the genes of these two QTLs through the following specific aims. First, we will narrow the QTLs using genomic, statistical and bioinformatic tools. Second, we will narrow the QTLs genetically. Third, we will test candidate genes in mice according to their sequence, expression and functions, and test their relevance to human CVD in association studies. Through this grant, we will find genes that regulate blood HDL cholesterol (the so-called "good cholesterol") levels. Drugs acting on these genes may increase HDL cholesterol, and decrease the incidence of cardiovascular disease.