Identification and Functional characterization of a gene influencing LDL-C on 5q

项目摘要 低密度脂蛋白胆固醇(LDL-C)水平升高与糖尿病的发生有关 心血管疾病(CVD)，而低密度脂蛋白水平的管理是心血管疾病的主要因素 预防。通过任何一种药物手段的生活方式实现低密度脂蛋白目标 可能会很有挑战性。有必要开发更便宜、更好的药物。 通过我们对阿米什人心血管健康的遗传学研究，我们最近发现了一个SNP 这与基因组区域的低密度脂蛋白水平密切相关(Chr 5q33，P=3.8？10-11) 不包含既定的胆固醇代谢基因。风险等位基因的每个副本都是 与低密度脂蛋白水平增加16毫克/分升有关。我们已经确定风险等位基因是 携带单个300kb单倍型，并且相关等位基因的所有携带者共享该单倍型 相同的单倍型在血统上是相同的，大概是通过引入阿米什人而产生的 许多世代以前，一个阿米什人的创建者。尽管推定的缺陷是 可能在非阿米什人中很少见，识别和表征它预计会很高 具有重要意义，因为它将阐明新的脂质生物学。 这项拟议的研究的目标是识别和表征功能变体和基因 导致低密度脂蛋白水平升高。我们已经对整个300kb的区域进行了测序 并确定了一小部分候选SNPs。我们在本申请中建议：(1)基因分型 在非阿米什人群中检测这些SNP与低密度脂蛋白的相关性；(2)评估 利用斑马鱼和基于细胞的模型研究相关区域的7个基因的功能；以及 (3)确定已确定的候选SNPs对基因功能的影响。成功 这些研究的完成有望导致一种新的胆固醇的鉴定 新陈代谢基因和发现新的生物学，可能对翻译有吸引力 开发预防和/或治疗动脉粥样硬化的新疗法。

Project Summary Elevated low density lipoprotein cholesterol (LDL-C) levels are associated with the development of cardiovascular disease (CVD), and management of LDL-C levels is a mainstay of CVD prevention. Attainment of LDL-C target goals through either lifestyle of pharmacologic means can be challenging. There is a need for the development of cheaper and better drugs. Through our genetic studies of cardiovascular health in the Amish, we recently identified a SNP that is strongly associated with LDL-C levels in a genomic region (chr 5q33, P=3.8 ¿ 10-11) that does not contain established cholesterol metabolism genes. Each copy of the risk allele is associated with a 16 mg/dl increase in LDL-C levels. We have established that the risk allele is carried on a single 300 kb haplotype and that all carriers of the associated allele share this same haplotype identical by descent, presumably through its introduction into the Amish population many generations ago by a single Amish founder. Although the putative defect is likely to be rare in non-Amish, identifying and characterizing it is expected to be of high significance because it will illuminate new lipid biology. The goal of the proposed study is to identify and characterize the functional variant and gene responsible for elevated LDL-C levels. We have already sequenced the entire 300 kb region and identified a small set of candidate SNPs. We propose in this application to: (1) genotype these SNPs in a non-Amish population and test each for association with LDL-C; (2) evaluate the function of the 7 genes in the associated region using zebrafish and cell-based models; and (3) establish the effects of the candidate SNPs already identified on gene function. Successful completion of these studies is expected to lead to the identification of a novel cholesterol metabolism gene and uncover new biology that may have translational appeal for the development of novel therapies to prevent and/or treat atherosclerosis.