Genetic Determinants: Low HDL, High Triglycerides, Obes*

描述(由申请人提供)： 在过去的10年里，土耳其进行了广泛的研究，以 确定心脏病的风险因素。涉及的研究约 来自土耳其六个不同地区的1万名土耳其男性和女性 确定了这一群体在几个方面都是独一无二的。土耳其人拥有 血浆高密度脂蛋白胆固醇(HDLC)水平几乎为 世界上任何人口(75%的男性和50%的女性 有高密度脂蛋白胆固醇水平&40 mg/dl)。平均高密度脂蛋白胆固醇水平低10-15毫克/分升 比西欧或美国人口中的人多。另外，土耳其人， 尤其是土耳其女性，有肥胖的倾向[38.8%的 女性的身体质量指数(BMI)和30公斤/M2]，男性和女性都有 有高甘油三酯血症的倾向。然而，低高密度脂蛋白胆固醇是独立的 肥胖或高甘油三酯血症。来自这个具有良好特征的样品 人口为探索遗传决定因素提供了一个独特的机会 与低高密度脂蛋白胆固醇、高甘油三酯血症的高患病率有关，以及 肥胖(代谢综合征的特征)。 该项目将分析冷冻血液样本中的DNA，以研究新的 候选基因靶点，可能提供对异常的洞察 描述了这一群体的特征。样本和大量的生物数据是 适用于所有10,000名参与者。在具体目标1中，我们将确定 酰辅酶A：二酰甘油酰基转移酶(DGAT)-I和-2和 在与ATP结合盒A I(ABCA I)相关的基因中 体重指数、高密度脂蛋白胆固醇和甘油三酯浓度的差异以及其他 血压等参数。这些研究将主要集中在 猪DGAT-I、DGAT-2和ABCAL基因启动子及其编码序列的多态性 具体目标2，我们将确定这些多态是否具有功能性 使用荧光素酶报告系统确定表达的意义 DGAT和ABCA1的多态形式，一种胆固醇外流测量 确定ABCA1编码序列多态的功能意义 和甘油三酯合成试验，以确定功能 DGAT-I和DGAT-2多态位点的意义多态的站点 将对来自三个亚组的DNA样本进行关联研究 土耳其人：(A)可能患有代谢综合征的个人，(B)个人 具有孤立的低高密度脂蛋白胆固醇(正常甘油三酯)，和(C)正常血脂 未受影响的对照。

DESCRIPTION (provided by applicant): Over the past 10 years, extensive studies have been conducted in Turkey to determine the risk factors for heart disease. Studies involving approximately 10,000 Turkish men and women from six different regions of Turkey have established that this population is unique in several ways. The Turks have the lowest plasma levels of high density lipoprotein cholesterol (HDL-C) of almost any population in the world (75 percent of the men and 50 percent of the women have HDL-C levels <40 mg/dl). The mean HDL-C levels are 10-15 mg/dl lower than those in Western European or American populations. In addition, Turks, especially Turkish women, have a tendency toward obesity [38.8 percent of the women have body mass index (BMI) >30 kg/M2], and both men and women have a tendency toward hypertriglyceridemia. The low HDL-C, however, is independent of obesity or hypertriglyceridemia. Samples from this well-characterized population provide a unique opportunity to explore the genetic determinants associated with the high prevalence of low HDL-C, hypertriglyceridemia, and obesity (characteristics of the metabolic syndrome). This project will analyze DNA from frozen blood samples to investigate new candidate gene targets that may provide insights into the abnormalities characterizing this population. The samples and extensive biodata are available on all 10,000 participants. In Specific Aim 1, we will identify polymorphisms in acyl CoA:diacylglycerol acyltranferase (DGAT)- I and -2 and in ATP-binding cassette A I (ABCA I) genes that are associated with differences in BMI, HDL-C, and triglyceride concentration, and other parameters such as blood pressure. These studies will focus significantly on promoter and coding sequence polymorphisms in DGAT-I and -2 and ABCAL In Specific Aim 2, we will determine whether the polymorphisms have functional significance by using a luciferase reporter system to determine expression of polymorphic forms of DGAT and ABCAI, a cholesterol efflux measurement to determine the functional significance of ABCAI coding sequence polymorphic sites, and a triglyceride synthesis assay to determine the functional significance of DGAT-I and -2 polymorphic sites. The polymorphic site association studies will be performed on DNA samples from three subgroups of Turks: (a) individuals likely to have the metabolic syndrome, (b) individuals with isolated low HDL-C (normal triglycerides), and (c) normolipidemic unaffected controls.