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

描述(申请人提供)：低密度脂蛋白胆固醇(LDL-C)水平升高与心血管疾病(CVD)的发展相关，管理低密度脂蛋白胆固醇(LDL-C)水平是预防心血管疾病的主要手段。通过任何一种生活方式或药物手段来实现低密度脂蛋白的目标可能是具有挑战性的。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，我们最近在一个基因组区域(chr 5q33，P=3.8x10-11)中发现了一个与低密度脂蛋白水平密切相关的SNP，该区域不包含已建立的胆固醇代谢基因。风险等位基因的每个拷贝都与低密度脂蛋白水平增加16毫克/分升有关。我们已经确定，危险等位基因是在单一的300kb单倍型上携带的，并且TE相关等位基因的所有携带者都具有相同的单倍型，这可能是通过许多代前由单一的阿米什创始人将其引入阿米什人群体而实现的。尽管这种假定的缺陷在非阿米什人中可能很少见，但我认为识别和描述它具有很高的意义，因为它将揭示新的脂类生物学。这项拟议研究的目标是确定和表征导致低密度脂蛋白水平升高的功能变异和基因。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SNP。在这一应用中，我们建议：(1)在非阿米什人群中对这些SNP进行分型，并测试每个SNP与低密度脂蛋白-C的关联；(2)使用斑马鱼和基于细胞的模型来评估相关区域中7个基因的功能；以及(3)建立已经确定的候选SNPs对基因功能的影响。这些研究的成功完成有望导致发现一种新的胆固醇代谢基因，并发现可能对开发预防和/或治疗动脉粥样硬化的新疗法具有翻译吸引力的新生物学。

DESCRIPTION (provided by applicant): 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 x 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 te 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 i 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 zebra fish 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.