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

描述（由申请人提供）：低密度脂蛋白胆固醇 (LDL-C) 水平升高与心血管疾病 (CVD) 的发生有关，控制 LDL-C 水平是预防 CVD 的支柱。通过任何生活方式或药物手段实现 LDL-C 目标可能具有挑战性。需要开发更便宜和更好的药物。通过对阿米什人心血管健康的遗传学研究，我们最近在不包含已确定的胆固醇代谢基因的基因组区域（chr 5q33，P=3.8 x 10-11）中发现了与 LDL-C 水平密切相关的 SNP。每个风险等位基因拷贝都与 LDL-C 水平增加 16 mg/dl 相关。我们已经确定风险等位基因携带在单个 300 kb 单倍型上，并且相关等位基因的所有携带者都具有相同的血统相同的单倍型，大概是通过一个阿米什创始人在许多代之前将其引入阿米什人群。尽管这种假定的缺陷在非阿米什人中可能很少见，但我预计对其进行识别和表征具有重要意义，因为它将阐明新的脂质生物学。拟议研究的目标是识别和表征导致 LDL-C 水平升高的功能变异和基因。我们已经对整个 300 kb 区域进行了测序，并确定了一小组候选 SNP。我们在此申请中建议：(1) 在非阿米什人群中对这些 SNP 进行基因分型，并测试每个 SNP 与 LDL-C 的关联； (2) 使用斑马鱼和基于细胞的模型评估相关区域7个基因的功能； (3) 确定已确定的候选 SNP 对基因功能的影响。这些研究的成功完成预计将导致新的胆固醇代谢基因的鉴定，并揭示新的生物学，这些生物学可能对开发预防和/或治疗动脉粥样硬化的新疗法具有转化吸引力。

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.