MOLECULAR BASIS OF HIGH DENSITY LIPOPROTEIN DEFICIENCY

点击翻译按钮获取中文摘要

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.