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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：
8614123
负责人：
BRAXTON D MITCHELL
金额：
$ 42.38万
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 2017-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8614123
关键词：
Accounting Alleles Amish Atherosclerosis Behavior Therapy Bioinformatics Biological Assay Biology Candidate Disease Gene Cardiovascular Diseases Cardiovascular system 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 Genetic Drift Genomics 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 chromosome 5q loss clinically relevant coronary artery calcification diet and exercise falls gene function genetic variant hypercholesterolemia in vivo interest new therapeutic target novel prevent public health relevance risk variant uptake

项目摘要

Project Summary 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 ¿ 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 the 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 is 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 zebrafish 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.

项目总结