GENETIC & BIOCHEMICAL PREDICTORS OF EARLY ATHEROGENESIS

基因

基本信息

批准号：
2673787
负责人：
PETER KWITEROVICH
金额：
$ 26.32万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1994
资助国家：
美国
起止时间：
1994-08-01 至 1999-07-31
项目状态：
已结题

项目摘要

Our overall objective is to study biochemical and genetic predictors of atherogenesis in youth. We will explore this objective in multiple generations of 61 large families (average size 19.8) previously ascertained through male and female probands with (N=32) and without (N=29) angiographically documented premature coronary artery disease (CAD). Traditional and non-traditional risk factors for CAD will be compared in relatives of the probands (211 children, 157 sibs, 189 grandchildren, 427 nieces and nephews). These risk factors include plasma levels of total, VLDL, LDL, HDL, HDL2 and HDL3 cholesterol, triglycerides, Lp(a), apoB, apoAI, lipoprotein particles (ApoAI only and LpCIII B and nonB), glucose, and insulin; Lp(a) polyforms and apoE isoforms; blood pressure, obesity, and cigarette smoking. Differences in the expression of these risk factors over time between children, adolescent young adults and adults will be studied. The heritability and penetrance of these traditional and non-traditional risk factors will be determined by segregation analysis; the influence of candidate genes, such as the lipoprotein lipase gene, on these risk factors and other metabolic and cellular abnormalities will be determined by linkage analysis; we will also look for specific mutations which may further explain these relationships. We will determine whether there are differences in endothelial cell function, as judged by high resolution ultrasound, in the relatives of the probands and examine which traditional and non-traditional risk factors best predict endothelial cell dysfunction. The biochemical expression of acylation stimulatory defects with the human serum basic proteins in cultured fibroblasts will be studied in several groups including: 1) CAD(-) proband, normal lipoprotein phenotype (N=6); 2 CAD(+) probands with hyperapoB and increased triglycerides (N=5); 3) CAD(+) probands with hyperapoB and normal triglycerides (N=6); 4) CAD(+) probands with type IV (N=6); and, 5) CAD(+) probands with normal lipoprotein phenotype (N=6). The concordance between the cellular defect and the presence of dyslipidemia, small, dense LDL, and CAD will be determined. In a subset of families, selected by probands with and without cellular acylation stimulatory defect, we will test the hypothesis that the defect is transmitted as a Mendelian dominant in the children and grandchildren of the probands. Our integrated hypothesis is that there is a cellular defect in a substantial proportion of families who develop CAD that is responsible for the pleiotropic phenotype of hyperapoB (and related syndromes), and furthermore, that this cellular defect is reflected in the expression of other risk factors that will accompany the syndrome.

我们的总体目标是研究的生化和遗传预测因子青年动脉粥样硬化。我们将在多个中探索这个目标几代人有61个大家庭（平均规模19.8）通过（n = 32）的男性和女性概率确定（n = 29）血管造影记录的早产冠状动脉疾病（CAD）。 CAD的传统和非传统风险因素将是比较证据的亲戚（211名儿童，157个同胞，189 孙子，427个侄女和侄子）。这些风险因素包括血浆总水平，VLDL，LDL，HDL，HDL2和HDL3胆固醇，甘油三酸酯，LP（A），APOB，APOAI，脂蛋白颗粒（仅APOAI，并且 LPCIII B和NONB），葡萄糖和胰岛素； LP（A）Polyforms和ApoE 同工型；血压，肥胖和吸烟。差异在儿童之间随着时间的流逝而表达这些危险因素时，将研究青少年的年轻人和成年人。遗传力和这些传统和非传统危险因素的外观将是通过隔离分析确定；候选基因的影响，例如脂蛋白脂肪酶基因，这些危险因素和其他代谢和细胞异常将由连锁决定分析;我们还将寻找可能进一步的特定突变解释这些关系。我们将确定是否有由高分辨率判断的内皮细胞功能的差异超声波，在概率的亲属中检查哪些传统和非传统风险因素最好预测内皮细胞功能障碍。酰化刺激的生化表达培养的成纤维细胞中人类血清碱性蛋白的缺陷将在多个组中进行研究，包括：1）cad（ - ）概率，正常脂蛋白表型（n = 6）; 2个带有超杆菌的CAD（+）概率和甘油三酸酯增加（n = 5）; 3）带有hyperapob和hyperapob和正常甘油三酸酯（n = 6）; 4）带有IV型的CAD（+）概率（n = 6）;和， 5）具有正常脂蛋白表型的CAD（+）概率（n = 6）。这细胞缺陷与血脂异常的存在之间的一致性，将确定小，密集的LDL和CAD。在一部分家庭中，由有或没有细胞酰化刺激的探针选择缺陷，我们将检验以下假设：缺陷被传播为孟德尔人在探险的儿童和孙子中占主导地位。我们综合的假设是A 大部分开发负责的CAD的家庭对于超杆菌（及相关综合征）的多效性表型，此外，这种细胞缺陷反映在综合征将伴随的其他风险因素。