Cloning QTL Genes for Plasma HDL Cholesterol

描述（由申请人提供）：动脉粥样硬化是缺血性心血管疾病（CVD）的病理基础，缺血性心血管疾病是工业化国家的主要死因。两条证据表明，高水平的血浆高密度脂蛋白胆固醇（HDL-C）可以预防CVD。首先，流行病学研究表明HDL-C水平与CVD发病率呈负相关。第二，在小鼠、兔子和人类中，血浆HDL-C水平升高与动脉粥样硬化减少有关。由于血浆HDL-C水平在很大程度上是由遗传决定的，数量性状基因座（QTL）定位已被用来定位HDL调节染色体（Chr）基因座。比较小鼠和人的HDL QTL发现，它们是一致的，因此，在小鼠中发现HDL-C QTL的基因可能会揭示人类HDL调节基因，这可能提供治疗靶点。我们的长期目标是寻找调节血浆HDL-C水平的新基因，为CVD提供新的治疗靶点。在本研究中，我们选择了一个位于第1代（Hdlq 33）和一个位于第6代（Hdlq 12）的HDL-C QTL，其鉴定标准是：（1）至少发现一个人类HDL-C QTL;（2）该QTL在多个杂交中发现，和/或与计算机模拟的HDL-C QTL一致; 3）QTL可以从紧密连锁的QTL中分离出来，这样我们就知道哪些杂交检测到了我们想要研究的QTL; 4）杂交涉及测序的菌株（B6、A、DBA/2和129），因为这样更容易发现序列差异;和5）其他遗传资源是可用的：同源株系、同源株系、重组近交株系。我们建议通过以下具体目标来鉴定这两个QTL的基因。首先，我们将使用基因组学、统计学和生物信息学工具缩小QTL。第二，我们将从遗传上缩小QTL。第三，我们将根据候选基因的序列、表达和功能在小鼠中进行测试，并在关联研究中测试它们与人类CVD的相关性。通过这项资助，我们将找到调节血液中高密度脂蛋白胆固醇（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HDL胆固醇，降低心血管疾病的发病率。

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.