Correlation of Lipoprotein Abnormalities in Childhood with the Risk for Atherosclerotic Coronary Heart Disease (CAD) in Adulthood (HDL function and polymorphism in HDL related genes)

儿童期脂蛋白异常与成年期动脉粥样硬化性冠心病 (CAD) 风险的相关性（HDL 功能和 HDL 相关基因多态性）

基本信息

批准号：
09670817
负责人：
OHTA Takao
金额：
$ 2.24万
依托单位：
Faculty of Medicine, University of The Ryukyus (1998)Kumamoto University (1997)
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1997
资助国家：
日本
起止时间：
1997 至 1998
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-09670817/
关键词：
LpA-I A-II Atherosclerosis LDL size Small LDL FERHDL CETP リポ蛋白

项目摘要

1. Small low density lipoprotein (LDL) particles are thought to be more atherogenic than larger LDL particles, although this association may depend on plasma triglyceride (TG) and high density lipoprotein (HDL) levels. To help prevent coronary artery disease (CAD), it may be useful to understand risk factors during childhood and adolescence. In the present study, we evaluated low density lipoprotein particle size (LDL-size) by gradient gel electrophoresis in 70 healthy children (30 boys and 40 girls) along with conventional lipid and lipoprotein parameters which are thought to affect LDL-size. The fractional and molar esterification rates (PER and MER) of cholesterol in plasma and HDL were also determined As expected, plasma levels of TG, HDL-cholesterol (HDL-C) and apoA-I were closely associated with LDL-sizes in both sexes. However, a closer association was found between FER in HDL (FERHDL) and LDL-size. In a stepwise multiple regression analysis, FERHDL alone accounted for 76 % and … More 41 % of the variability in LDL-size in boys and girls, respectively. MER in HDL accounted for additional 4 % and 19 % in boys and girls, respectively. Other parameters, including plasma TG, HDL-C and apoA-I had no significant additional effects. Thus, the determination of FERHDL is useful to predict the particle size of LDL in children.2. Low plasma E{DL-C is a major risk factor for CAD in adults. In the field of pediatrics, subjects with low plasma HDL-C are often found among obese or dyslipidemic children. However, it is not clear whether low HDL-C in children should be considered a risk factor for CAD.The purpose of this study was to evaluate the risk for CAD in children with low HDL-C by comparing their lipid and apolipoprotein levels and physicochemical characteristics of their HDL with those of age-matched children with normal HDL-C and CAD patients with low HDL-C.Plasma lipids and apolipoproteins were measured in 206 dyslipidemic children (dyslipidemic), 65 obese children (obese), 93 CAD patients with low HDL-C (<40 mg/dL) and 128 children with normal HDL-C.To evaluate the physicochemical characteristics of HDL, molar and fractional esterification rates of cholesterol in plasma (MERplasma and FERplasma) and HDL (MERHDL and FERHDL) were determined in 128 children with normal HDL-C, 71 dyslipidemic, 33 obese and 93 CAD.Compared with controls, children with low HDL-C showed atherogenic profiles of lipid and apolipoprotein levels and physicochemical characteristics of HDL.Therefore, we next examined the differences in lipid and apolipoprotein profiles between children with low HOL-C and CAD patients with low HDL-C.We studied two groups of subjects based on the HDL-C level (Group I : <30 mg/dL, Group II 30l-HDL-C<40mgldL). Compared with CAD, Group I children showed less atherogenic apolipoprotein profiles (lower apoB and higher ratio of apoA-I to apoB). Similar findings were also found in Group II children, but the differences were less prominent than those in Group I children. FERHDL in children with low HDL-C were similar to those in CAD.These findings suggest that the physicochemical characteristics of HbL in children with low HDL-C are similar to those in CAD, but the abnormalities of apoB-containing lipoproteins are milder than those in CAD patients. Thus, if we could prevent further changes in the nature of apoB-containing lipoproteins, children with low HDL-C might not become high risk for CAD in later life.3.Gene analysis for CETP deficiency was carried out by PCR-RFLP for D442G and Intl4A.DNA was extracted from dried blood spots from dyslipidernic children detected by mass screening. Nutritional analysis was performed by clinical dietitian in Kumamoto University hospital. Gene analysis for CETP was done in 181 dyslipidemic children. Children with Intl4A was not found However, we could find 13 children with heterozygote for D442G mutation. Their plasma levels of HDL-C, apoA-I and apoA-II were similar to those in children with no mutations of CETP gene. These results indicate that CETP deficiency in young children may not affect the plasma concentrations of HDL.Other factor might be required to raise the plasma levels of HDL. Less

1. 小的低密度脂蛋白 (LDL) 颗粒被认为比较大的 LDL 颗粒更容易导致动脉粥样硬化，尽管这种关联可能取决于血浆甘油三酯 (TG) 和高密度脂蛋白 (HDL) 水平，以帮助预防冠状动脉疾病 (CAD)。，这可能有助于了解儿童期和青春期的危险因素。在本研究中，我们通过梯度凝胶电泳评估了 70 名健康儿童（30 名男孩和 30 名男孩）的低密度脂蛋白颗粒大小 (LDL-size)。 40 名女孩）以及被认为影响 LDL 大小的传统脂质和脂蛋白参数，还测定了血浆和 HDL 中胆固醇的分数和摩尔酯化率（PER 和 MER）。正如预期的那样，还测定了 TG、HDL 胆固醇的血浆水平。 (HDL-C) 和 apoA-I 与两性的 LDL 大小密切相关，然而，HDL 中的 FER (FERHDL) 与 LDL 大小之间存在更密切的关联。逐步多元回归分析显示，FERHDL 单独占男孩和女孩 LDL 大小变异的 76% 和 41%，HDL 中的 MER 分别占男孩和女孩的 4% 和 19%。，其中血浆TG、HDL-C和apoA-I没有显着的附加影响，因此，FERHDL的测定有助于预测儿童LDL的粒径。2． E{DL-C 是成人 CAD 的主要危险因素。在儿科领域，血浆 HDL-C 低的受试者常见于肥胖或血脂异常的儿童，但尚不清楚儿童中是否存在低 HDL-C。应被视为 CAD 的危险因素。本研究的目的是通过比较低 HDL-C 儿童的脂质和载脂蛋白水平以及 HDL 的理化特征与年龄匹配的 HDL-C 儿童的 CAD 风险。正常 HDL-C 和低 HDL-C CAD 患者。测量了 206 名血脂异常儿童 (dyslipidemic)、65 名肥胖儿童 (obese)、93 名低 HDL-C (<40 mg/dL) CAD 患者和128例HDL-C正常儿童，评价HDL理化特性、血浆胆固醇摩尔酯化率和分数酯化率在 128 名 HDL-C 正常、71 名血脂异常、33 名肥胖和 93 名 CAD 儿童中测定了 HDL（MERplasma 和 FERplasma）和 HDL（MERHDL 和 FERHDL）。与对照组相比，低 HDL-C 儿童的脂质和载脂蛋白水平显示出动脉粥样硬化特征HDL 和理化特征。因此，我们接下来检查了低 HOL-C 儿童之间脂质和载脂蛋白谱的差异我们根据HDL-C水平研究了两组受试者（第一组：<30mg/dL，第二组30l-HDL-C<40mgldL）与CAD相比，第一组儿童。在第 II 组儿童中也发现了类似的结果，但差异不如第 I 组显着。低HDL-C儿童的FERHDL与CAD相似。这些研究结果表明，低HDL-C儿童的HbL理化特征与CAD相似，但含apoB脂蛋白的异常较轻。因此，如果我们能够阻止含 apoB 脂蛋白性质的进一步变化，HDL-C 水平较低的儿童可能不会成为 CAD 的高风险人群。 3.通过PCR-RFLP对D442G和Intl4A进行CETP缺陷基因分析。从大规模筛查检测到的血脂异常儿童的干血斑中提取DNA，并由熊本大学基因医院临床营养师进行营养分析。对 181 名血脂异常儿童进行了 CETP 分析，未发现 Intl4A 儿童，但我们发现 13 名儿童有 D442G 杂合子。他们的血浆HDL-C、apoA-I和apoA-II水平与CETP基因未突变的儿童相似。这些结果表明，幼儿CETP缺乏可能不会影响血浆HDL浓度。可能需要较少的血浆 HDL 水平。