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

描述（由申请方提供）：低密度脂蛋白胆固醇（LDL-C）水平升高与心血管疾病（CVD）的发生相关，LDL-C水平的管理是CVD预防的主要措施。通过任何一种生活方式或药理学手段达到LDL-C目标都具有挑战性。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，该SNP与基因组区域（chr 5 q33，P=3.8 x 10-11）中的LDL-C水平密切相关，该基因组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一个单一的300 kb的单倍型和所有的te相关等位基因的运营商共享相同的单倍型相同的血统，大概是通过它引入到阿米什人人口许多代前由一个单一的阿米什创始人。尽管这种假定的缺陷在非阿米什人中可能很罕见，但鉴定和表征它预计具有很高的意义，因为它将阐明新的脂质生物学。拟议研究的目的是鉴定和表征导致LDL-C水平升高的功能变体和基因。我们已经对整个300 kb区域进行了测序，并确定了一小部分候选SNP。在本申请中，我们建议：（1）在非阿米什人群体中对这些SNP进行基因分型，并测试每个SNP与LDL-C的相关性;（2）使用斑马鱼和基于细胞的模型评估相关区域中7个基因的功能;以及（3）建立已经鉴定的候选SNP对基因功能的影响。这些研究的成功完成预计将导致一个新的胆固醇代谢基因的鉴定和发现新的生物学，可能有翻译的新疗法，以预防和/或治疗动脉粥样硬化的发展的吸引力。

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.