GENE/DIET EFFECTS ON PLASMA LIPOPROTEIN LEVELS

描述（由申请人提供）：心血管疾病（CVD）是美国发病率和死亡率的主要原因，其风险由不可改变的（即遗传）和可改变的因素（即血脂水平）决定。低水平的高密度脂蛋白胆固醇（HDL-C）与心血管疾病风险增加有关，这一点已经得到了充分的证实。HDL代谢的关键决定因素是肝脂肪酶（HL），一种催化脂蛋白中甘油三酯和磷脂水解的酶。在肝脂肪酶（LIPC）基因-514位存在常见的C/T多态性。-514TT基因型与HL活性降低约40%和HDL-C水平升高相关。然而，这种效应在人群中是可变的，这表明基因-环境相互作用。该基金早期的主要发现之一是-514多态性显示了白人中高密度脂蛋白c水平和饮食脂肪摄入量之间的统计学显著相互作用。此外，我们在亚洲人群中重复了这一发现。有待证明的是，当受试者改变他们的饮食脂肪摄入量时，这些相互作用是否会发生，如果是这样，涉及到什么机制。因此，本建议的主要目标是使用介入设置来彻底评估LIPC基因变异，饮食脂肪摄入量和血浆脂质水平变化，炎症标志物和内皮功能之间的相互作用。此外，我们假设少数民族，如西班牙裔，由于-514 T等位基因（约0.36）的富集，更容易受到这些基因-饮食相互作用的影响。因此，我们提出了一项随机、交叉、两阶段饮食干预，旨在评估摄入不同水平的膳食脂肪（分别为15%和37%，各6周）对加勒比海西班牙裔受试者（n=80； 40 CC和40 TT）血浆HDL相关指标的影响。我们的主要假设是，CC受试者对以脂肪形式消耗的能量百分比的增加与HDL-C水平的增加有反应。相反，在TT受试者中，这种饮食改变导致HDL-C水平下降和内皮功能恶化。因此，当T受试者食用高脂肪饮食时，心血管疾病的风险会增加。此外，考虑到西班牙裔中T等位基因的高频率，这种相互作用可能解释了文化适应后心血管疾病风险增加的一些原因。这种基于证据的知识将有助于制定更有效的饮食建议，以减少健康差异，并更好地预防心血管疾病。

DESCRIPTION (provided by applicant): Cardiovascular diseases (CVD) are the major causes of morbidity and mortality in the US and their risks are determined by non-modifiable (i.e., genetic) and modifiable factors (i.e., plasma lipid levels). It is well established that low levels of high-density lipoprotein cholesterol (HDL-C) are associated with increased CVD risk. A key determinant of HDL metabolism is hepatic lipase (HL), an enzyme that catalyses the hydrolysis of triglycerides and phospholipids in lipoproteins. Within the hepatic lipase (LIPC) gene at position -514 exists a common C/T polymorphism. The -514TT genotype is associated with an approximate 40% decrease in HL activity and increased HDL-C levels. However, this effect is variable among populations, suggesting gene- environment interactions. One of this grant's earlier key findings is that the -514 polymorphism shows a statistically significant interaction between HDL-C levels and dietary fat intake in Whites. Moreover, we replicated the findings in an Asian population. What remains to be demonstrated is whether these interactions occur when subjects modify their dietary fat intake and if so, what mechanisms are involved. Thus, the primary goal of this proposal is to use an interventional setting to thoroughly evaluate interactions between LIPC gene variants, changes in dietary fat intake and plasma lipid levels, inflammation markers and endothelial function. Moreover, we hypothesize that minorities, such as Hispanics, due to the enrichment of the -514 T allele (approximately 0.36) are more susceptible to the effects of these gene-diet interactions. Hence, we propose a randomized, cross over, two-phase diet intervention aimed at assessing the impact of consuming different levels of dietary fat (15% and 37%, respectively, 6 weeks each) on plasma HDL related measures in Caribbean Hispanic subjects (n=80; 40 CC and 40 TT). Our main hypothesis is that CC subjects respond to increases in the % of energy consumed as fat with increases in HDL-C levels. Conversely, in TT subjects, such dietary change results in decreases in HDL-C levels and worsening of endothelial function. Therefore, T subjects will have an elevated CVD risk when consuming high fat diets. Moreover, given the high frequency of the T allele in Hispanics, this interaction could account for some of the increase in CVD risk seen after acculturation. This evidence-based knowledge will contribute to a rational approach toward more effective dietary recommendations aimed to decrease health disparities and to a better CVD prevention.