GENE/DIET EFFECTS ON PLASMA LIPOPROTEIN LEVELS

冠心病（CHD）仍然是我们社会中导致死亡和残疾的主要原因。每年，美国大约有50万人死于这种疾病，全球有720万人死于这种疾病。死于冠心病的女性和男性一样多。减少冠心病主要病因的机会就在眼前。通过注重预防，我们可以对人们的健康产生重大影响。然而，我们对营养充足性、营养-疾病相互作用以及实施当前建议的有效策略的认识存在重大差距，这些建议具有广泛认可的减轻美国人口负担的潜力。此外，我们对通过与营养物质相互作用的方式直接或间接影响风险的特定基因和遗传变异知之甚少。因此，美国卫生组织指定的目标之一是确定可能在导致重大疾病或保护个人免受此类疾病的原因中发挥关键作用的众多基因的特征，并调查它们与营养物质的相互作用。同样，必须确定影响个体对特定饮食因素易感性的特定多态性基因的作用。因此，本建议的主要目的是：1。评估候选基因[过氧化物酶体增殖物激活受体（PPARA和PPARG），雌激素受体（ESRA），甾醇调节元件结合蛋白（SREBP1和SREBP2）， SREBP裂解激活蛋白（SCAP）， 3-羟基-3-甲基戊二酰辅酶a还原酶（HMGCR），清除率受体B-I类（SRBI），肠道脂肪酸结合蛋白（FABP2），和atp结合盒1 (ABC1)]在自由生活人群中与血脂变异性和冠心病相关。研究这些基因变异和饮食因素之间的相互作用。关于这种基因-饮食相互作用的信息将为饮食因素调节脂质代谢的机制提供重要线索。提出的候选基因有助于血浆低密度脂蛋白胆固醇（LDL，C），高密度脂蛋白胆固醇（HDL-C）和甘油三酯（TG）水平的变化。研究人群包括参加Framingham Offspring （FOS）和OMNI （minority）研究的受试者（约3,180人）。主要结局是LDL- c、HDL-C、TG、残留物样颗粒- c水平、脂蛋白颗粒大小和LDL氧化测量。次要结局是碳水化合物代谢相关指标（即葡萄糖和胰岛素水平）。我们的主要假设是，这些位点的遗传变异与血浆脂质测量的变异性有关，从而决定了冠心病的风险。这些影响受到饮食和行为因素的调节。这些知识将促进基因筛查小组的产生，这将有助于对冠心病风险的个人评估和饮食治疗咨询。

Coronary heart disease (CHD) remains the leading cause of death and disability in our society. Every year, approximately 500,000 deaths in the U.S. and 7.2 million globally are caused by this disease. As many women die from CHD as do men. The opportunity to reduce the major causes of CHD is at hand. By focusing on prevention, we can have a major impact on people's health. However, major gaps exist in our knowledge about nutritional adequacy, nutrient-disease interactions, and effective strategies to implement the current recommendations, which have the widely recognized potential to decrease the burden of the American population. Moreover, we know little about specific genes and genetic variations that affect risk directly and indirectly by the way they interact with nutrients. Therefore, one of the goals specified by U.S. Health Organizations is to characterize the numerous genes that likely play a critical role in the causation of major diseases or the protection of individuals from such diseases and to investigate their interactions with nutrients. Similarly, the roles of specific polymorphic forms of genes that influence individual susceptibility to specific dietary factors must be identified. Hence, the primary aims of this proposal are: 1. To evaluate whether polymorphisms at the proposed candidate genes [Peroxisome Proliferator-Activated Receptors (PPARA and PPARG), Estrogen Receptor (ESRA), Sterol Regulatory Element-Binding Proteins (SREBP1 and SREBP2), SREBP cleavage-activating protein (SCAP), 3- Hydroxy-3-Methylglutaryl-CoA Reductase (HMGCR), Scavenger Receptor Class B-I (SRBI), Intestinal Fatty Acid-Binding Protein (FABP2), and ATP-Binding Cassette 1 (ABC1)] are associated with plasma lipid variability and CHD in a free-living population, and 2. To examine interactions between those gene variants and dietary factors. Information about such gene-diet interactions will provide significant clues about the mechanisms by which dietary factors regulate lipid metabolism. The candidate genes proposed contribute to variation in plasma low-density lipoprotein cholesterol (LDL,C), high-density lipoprotein cholesterol (HDL-C) and triglyceride (TG) levels. The study population consists of subjects participating in the Framingham Offspring (FOS) and OMNI (Minorities) studies (n approximately 3,180). The primary outcomes are LDL-C, HDL-C, TG, remnant-like particle-C levels, lipoprotein particle size, and measures of LDL oxidation. Secondary outcomes are carbohydrate metabolism- related measures (i.e., glucose and insulin levels). Our main hypothesis is that genetic variants at these loci are associated with variability of plasma lipid measures, thus determining CHD risk. These effects are modulated by dietary and behavioral factors. This knowledge will facilitate the generation of genetic screening panels that will assist in individual assessment of CHD risk and dietary therapeutic counseling.