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

影响 5q LDL-C 基因的鉴定和功能表征

基本信息

批准号：
9341571
负责人：
BRAXTON D MITCHELL
金额：
$ 3.7万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-01-15 至 2016-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9341571
关键词：
Accounting Alleles Amish Atherosclerosis Behavior Therapy Bioinformatics Biological Assay Biology Candidate Disease Gene Cardiovascular Diseases Cell Line Cell physiology Cells Cholesterol Cholesterol Homeostasis Chromosomes Code Defect Development Diet Disease Management Embryo Founder Generation Framingham Heart Study Gene Expression Gene Frequency Generations Genes Genetic Drift Genetic study Genomic Segment Genotype Goals Haplotypes Health Heart Diseases Hot Spot In Vitro LDL Cholesterol Lipoproteins Lead Life Style Lipids Lipoproteins Liver Low-Density Lipoproteins Measures Metabolism Modeling Pharmaceutical Preparations Population RNA Reporter Genes Research Risk Factors Role SNP genotyping System Testing Transcript Variant Whole Blood Zebrafish base cardiovascular disorder prevention cardiovascular disorder risk cardiovascular health chromosome 5q loss clinically relevant coronary artery calcification diet and exercise falls gene function genetic variant hypercholesterolemia identity by descent in vivo interest knock-down new therapeutic target novel novel therapeutics overexpression prevent risk variant study population uptake

项目摘要

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.

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CVD预防的支柱。通过药物手段的任何一种生活方式，实现LDL-C目标目标都可能具有挑战性。需要开发更便宜，更好的药物。通过我们对阿米什人心血管健康的遗传研究，我们最近确定了与基因组区域中LDL-C水平密切相关的SNP（CHR 5Q33，P = 3.8 x 10-11），该SNP不包含已建立的胆固醇代谢基因。风险等位基因的每个副本都与LDL-C水平增加16 mg/dl有关。我们已经确定，风险等位基因是单个300 kb单倍型的携带，并且所有te相关等位基因的载体都通过下降相同，这是同一单倍型相同的，大概是通过其几代人以前的一个阿米什人的创始人引入了阿米什人的引入。尽管假定的缺陷在非阿米什人中可能很少见，但我希望它具有很高的意义，因为它会阐明新的脂质生物学。拟议的研究的目的是识别和表征负责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。我们在此应用中提出：（1）基因型这些SNP在非Amish人群中，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中7个基因的功能；（3）建立已经鉴定出的候选SNP对基因功能的影响。预计这些研究的成功完成将导致鉴定出一种新型胆固醇代谢基因，并发现新的生物学，这些新生物学可能会引起人们对预防和/或治疗动脉粥样硬化的新疗法的转化吸引力。