MOLECULAR BASIS OF HIGH DENSITY LIPOPROTEIN DEFICIENCY

高密度脂蛋白缺乏症的分子基础

• 批准号: 2854266
• 负责人: ERNST JOHN SCHAEFER
• 金额: $ 30.04万
• 依托单位: TUFTS MEDICAL CENTER
• 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 2002-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2854266
• 关键词: antihyperlipoproteinemic agent; blood lipoprotein metabolism; cholesterol; clinical research; coronary disorder; 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; veterans

Coronary heart disease (CHD) is a major cause of death and disability in our society. A plasma high density lipoprotein cholesterol (HDL-C) concentration of less than 35 mg/dl has been defined as a major independent CHD risk factor. Approximately half of the variation in HDL-C concentrations is determined by environmental factors, such as diet, alcohol intake, and exercise, but there is also a strong genetic component. A number of mutations have been reported in the genes for key enzymes involved in the regulation of plasma HDL-C concentrations, including cholesteryl ester transfer protein (CETP), hepatic lipase (HL), lecithin:cholesterol acyltransferase (LCAT), and lipoprotein lipase (LPL). However, only for LPL have common mutations been identified in the general population. Two of these, the Asn291 yields Ser and Asp9 yields Asn mutations, decrease LPL activity, raising triglycerides and lowering HDL-C, while, conversely, the third mutation, Ser447X, enhances LPL activity, reducing triglycerides and elevating HDL-C. Although these mutations have been shown to affect CHD risk, their frequency in patients with HDL deficiency has not yet been assessed. Hence, the purpose of this research project is to: 1) isolate DNA from 2531 men participating in the prospective Veterans Administration HDL Intervention Trial (HIT), all of whom have an HDL-C level of less than 40 mg/dl and established CHD, 2) determine the frequencies of the three common LPL mutations in this population and compare these data with those of age-matched men in the Framingham Offspring Study (FOS) having no evidence of CHD, and, lastly 3) assess the relationships between these three LPL variants and response to gemfibrozil (n=1265) and/or an oral fat challenge (n=600) in HIT subjects. We hypothesize that there will be significantly higher frequencies of the Asn291 yields Ser and Asp9 yields Asn mutations and a significantly lower frequency of the Ser447X mutation in the HIT study group relative to the FOS group. In FOS controls, we have shown the frequencies of these LPL mutations to be 0.026, 0.028, and 0.168, respectively, in the heterozygous state. Moreover, we hypothesize that those HIT subjects with either of the former two mutations will be less responsive to gemfibrozil therapy in terms of triglyceride lowering and HDL-C raising, as well as less efficient at handling an oral fat challenge, whereas those with the latter mutation will be more responsive and more efficient in this regard. This research will provide us with important information about the role of LPL mutations in the determination of low plasma HDL-C concentrations.

冠心病（CHD）是导致死亡和残疾的主要原因。 血浆高密度脂蛋白胆固醇（HDL-C）浓度低于35 mg/dl已被定义为一个主要的独立的CHD危险因素。 HDL-C浓度的变化大约有一半是由环境因素决定的，如饮食，酒精摄入量和运动，但也有很强的遗传成分。 据报道，参与血浆HDL-C浓度调节的关键酶基因中存在许多突变，包括胆固醇酯转移蛋白（CETP）、肝脂肪酶（HL）、卵磷脂：胆固醇酰基转移酶（LCAT）和脂蛋白脂肪酶（LPL）。 然而，只有LPL在一般人群中发现了常见的突变。 其中两个，Asn 291产生Ser和Asp 9产生Asn突变，降低LPL活性，提高甘油三酯和降低HDL-C，而相反，第三个突变，Ser 447 X，增强LPL活性，降低甘油三酯和升高HDL-C。 虽然这些突变已被证明会影响CHD风险，但其在HDL缺乏症患者中的频率尚未评估。 因此，本研究项目的目的是：1）从参与前瞻性退伍军人管理局HDL干预试验（HIT）的2531名男性中分离DNA，所有这些人的HDL-C水平低于40 mg/dl并确定了CHD，2）确定这一人群中三种常见LPL突变的频率，并将这些数据与Fractionary Offspring研究中年龄匹配的男性的数据进行比较（FOS），最后3）评估这三种LPL变体与HIT受试者对吉非罗齐（n=1265）和/或口服脂肪挑战（n=600）的反应之间的关系。 我们假设HIT研究组中Asn 291产生Ser和Asp 9产生Asn突变的频率显著高于FOS组，而Ser 447 X突变的频率显著低于FOS组。 在FOS对照组中，我们已经证明这些LPL突变的频率在杂合状态下分别为0.026、0.028和0.168。 此外，我们假设，具有前两种突变之一的HIT受试者在甘油三酯降低和HDL-C升高方面对吉非罗齐治疗的反应较低，并且在处理口服脂肪挑战方面的效率较低，而具有后一种突变的受试者在这方面的反应更高，效率更高。 这项研究将为我们提供关于LPL突变在测定低血浆HDL-C浓度中的作用的重要信息。