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）的发展有关，而LDL-C水平的管理是预防CVD的主要手段。通过生活方式或药物手段达到LDL-C目标是具有挑战性的。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研究，我们最近发现了一个与基因组区域（chr 5q33， P=3.8 x 10-11）的LDL-C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。风险等位基因的每一个拷贝都与LDL-C水平增加16毫克/分升有关。我们已经确定，风险等位基因携带在一个300 kb的单倍型上，并且所有相关等位基因的携带者都具有相同的单倍型，可能是通过许多代以前由一个阿米什创始人引入阿米什人群而遗传的。虽然这种假定的缺陷在非阿米什人中很可能是罕见的，但识别和描述它将具有很高的意义，因为它将阐明新的脂质生物学。该研究的目的是确定和表征导致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，并确定了一小部分候选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，并测试它们与LDL-C的关系；(2)利用斑马鱼和细胞模型对相关区域7个基因的功能进行评价；(3)确定已鉴定的候选snp对基因功能的影响。这些研究的成功完成有望导致新的胆固醇代谢基因的鉴定，并揭示可能对开发预防和/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.