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 心血管疾病（CVD），和LDL-C水平的管理是CVD的支柱 预防通过生活方式或药理学手段达到LDL-C目标 会很有挑战性需要开发更便宜和更好的药物。 通过我们对阿米什人心血管健康的遗传研究，我们最近发现了一个SNP， 与基因组区域（chr 5 q33，P=3.8 <$10 -11）中的LDL-C水平密切相关， 不含已确定的胆固醇代谢基因。风险等位基因的每个拷贝 与LDL-C水平升高16 mg/dl相关。我们已经确定风险等位基因是 携带在单个300 kb单倍型上，并且相关等位基因的所有携带者都共享这一点。 相同的单倍型相同的血统，大概是通过其引入到阿米什人 由一位阿米什创始人在几代人前创造的。虽然假定的缺陷是 在非阿米什人中可能很少见，但识别和表征它的可能性很高 重要性，因为它将阐明新的脂质生物学。 这项研究的目的是鉴定和表征功能变体和基因， 导致LDL-C水平升高。我们已经测序了整个300 kb区域 并确定了一小组候选SNP。在本申请中，我们提出：（1）基因型 在非阿米什人群体中检测这些SNP，并检测每个SNP与LDL-C的相关性;（2）评估 使用斑马鱼和基于细胞的模型研究相关区域中7个基因的功能;以及 (3)确定已经确定的候选SNP对基因功能的影响。成功 这些研究的完成有望导致鉴定一种新的胆固醇 代谢基因和发现新的生物学，可能有翻译的呼吁， 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.