GENE/DIET EFFECTS ON PLASMA LIPOPROTEIN LEVELS

描述(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(即遗传的)和可改变的因素(即血脂水平)决定。众所周知，低水平的高密度脂蛋白胆固醇(高密度脂蛋白胆固醇)与心血管疾病风险增加有关。高密度脂蛋白代谢的关键决定因素是肝脂酶(HL)，这是一种催化脂蛋白中甘油三酯和磷脂水解的酶。在肝脂酶(LIPC)基因-514位存在常见的C/T多态。-514TT基因与HL活性降低约40%和高密度脂蛋白胆固醇水平升高有关。然而，这种影响在不同的种群中是不同的，这表明了基因和环境的相互作用。这项资助的早期关键发现之一是，-514基因多态在白人中显示出高密度脂蛋白水平和饮食脂肪摄入量之间具有统计学意义的相互作用。此外，我们在亚洲人群中复制了这一发现。有待证实的是，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，涉及什么机制。因此，这项建议的主要目标是使用干预性环境来彻底评估LIPC基因变异、膳食脂肪摄入量和血脂水平的变化、炎症标志物和内皮功能之间的相互作用。此外，我们假设，少数族裔，如西班牙裔，由于-514 T等位基因的丰富(约0.36)，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，旨在评估摄取不同水平的膳食脂肪(分别为15%和37%，每6周)对加勒比海拉美裔受试者(n=80；40CC和40TT)血浆高密度脂蛋白相关指标的影响。我们的主要假设是，CC受试者对作为脂肪消耗的能量百分比的增加以及高密度脂蛋白胆固醇水平的增加做出反应。相反，在TT受试者中，这种饮食变化会导致高密度脂蛋白-C水平下降和内皮功能恶化。因此，T受试者在食用高脂肪饮食时，心血管疾病的风险将会增加。此外，考虑到拉美裔美国人中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部分原因。这种以证据为基础的知识将有助于以合理的方法提出更有效的饮食建议，旨在减少健康差距和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.