Molecular Basis of High Density Lipoprotein Deficiency

高密度脂蛋白缺乏症的分子基础

• 批准号: 7054062
• 负责人: ERNST JOHN SCHAEFER
• 金额: $ 31.46万
• 依托单位: TUFTS UNIVERSITY BOSTON
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-04-01 至 2009-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7054062
• 关键词: blood lipoprotein metabolism; cholesterol; clinical research; coronary disorder; gemfibrozil; gene mutation; genetic susceptibility; genotype; high density lipoproteins; human genetic material tag; human population genetics; human subject; lipoprotein disorder; lipoprotein lipase; male; metabolism disorder chemotherapy; molecular pathology; statistics /biometry; triglycerides

DESCRIPTION (provided by applicant): A low level of high density lipoprotein cholesterol (HDL-C) is an independent risk factor for coronary heart disease (CHD). It is estimated that more than 50% of the variation in HDL-C levels in humans is genetically determined. There is great interest in the concept that common genetic variants contribute to inherited differences in the susceptibility to common diseases. One promising approach to address this issue is to relate variation in DNA sequence with patient characteristics in population-based association studies. We are proposing to identify allelic variants associated with the low HDL trait, using samples from the Veterans Affairs HDL Intervention Trial (VA-HIT, cases), a study designed to explore the benefits of HDL-raising with gemfibrozil in men having low HDL-C (<40 mg/dL), normal LDL-C (<140 mg/dL) and known CHD, and the Framingham Offspring Study (FOS, controls). Our primary aims are to identify: 1) susceptibility loci for the low HDL trait, 2) allelic variants associated with levels of apolipoproteinA-l-containing HDL subspecies, and 3) allelic variants associated with response to gemfibrozil in VA-HIT. For Aim 1, we will examine biological (n=38) and positional (n=3) candidates. The former will include genes involved in HDL metabolism, insulin resistance and inflammation, while the latter will be selected on the basis of results from genome-wide linkage scans for quantitative trait loci associated with HDL-C levels in FOS. For each candidate, we will use HapMap data in order to select a maximally informative set of SNPs (tagSNPs), which will allow us to resolve >80% of all haplotypes. Based on this algorithm, we will genotype 1 SNP per 2500 bp across each candidate gene/region. To address the issue of population stratification, we will employ a structured association approach, using a set of 250 markers that has the ability to detect modest amounts of stratification. The results of this work will provide important insight into the contribution of allelic variation in the pathways of HDL metabolism, inflammation, and insulin resistance to the complex phenotype of low HDL-C.

描述（由申请人提供）：低水平的高密度脂蛋白胆固醇（HDL-C）是冠心病（CHD）的独立危险因素。据估计，人类HDL-C水平的变化超过50%是由遗传决定的。有很大的兴趣的概念，共同的遗传变异有助于遗传差异的易感性常见疾病。解决这个问题的一个有希望的方法是在基于人群的关联研究中将DNA序列的变异与患者特征联系起来。我们建议使用退伍军人事务部HDL干预试验（VA-HIT，病例）和FOS后代研究（FOS，对照）的样本来鉴定与低HDL性状相关的等位基因变体，该研究旨在探索吉非罗齐升高HDL在低HDL-C（<40 mg/dL）、正常LDL-C（<140 mg/dL）和已知CHD男性中的益处。我们的主要目的是鉴定：1）低HDL性状的易感基因座，2）与含载脂蛋白A-I的HDL亚种的水平相关的等位基因变体，和3）与VA-HIT中对吉非罗齐的应答相关的等位基因变体。对于目标1，我们将检查生物（n=38）和位置（n=3）候选人。前者将包括参与HDL代谢、胰岛素抵抗和炎症的基因，而后者将根据与FOS中HDL-C水平相关的数量性状基因座的全基因组连锁扫描结果进行选择。对于每个候选人，我们将使用HapMap数据以选择最大信息量的SNP（tagSNP）集，这将使我们能够解析>80%的所有单倍型。基于该算法，我们将在每个候选基因/区域中每2500 bp对1个SNP进行基因分型。为了解决人口分层的问题，我们将采用结构化关联方法，使用一组250个标记，有能力检测适度的分层。这项工作的结果将提供重要的洞察力的等位基因变异的HDL代谢途径，炎症和胰岛素抵抗的低HDL-C的复杂表型的贡献。