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）

• 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

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）颗粒被认为比大的LDL颗粒更容易致动脉粥样硬化，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。为了预防冠状动脉疾病（CAD），了解儿童和青少年时期的危险因素可能是有用的。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40名女孩）的低密度脂蛋白颗粒大小（LDL-size）以及被认为影响LDL-size的常规脂质和脂蛋白参数。血浆和高密度脂蛋白胆固醇的分数和摩尔酯化率（PER和MER）也被测定。正如预期的那样，两性血浆中TG、HDL-胆固醇（HDL- c）和apoA-I水平与ldl大小密切相关。然而，高密度脂蛋白（FERHDL）与ldl大小之间存在更密切的关联。在逐步多元回归分析中，单独的FERHDL分别占男孩和女孩ldl大小变异的76%和41%。在男孩和女孩中，高密度脂蛋白中的MER分别占4%和19%。其他参数，包括血浆TG、HDL-C和apoA-I没有明显的额外影响。因此，FERHDL的测定有助于预测儿童LDL的粒径。低血浆E - DL-C是成人冠心病的主要危险因素。在儿科领域，低血浆HDL-C常见于肥胖或血脂异常的儿童。然而，目前尚不清楚儿童低HDL-C是否应被视为冠心病的危险因素。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的物理化学特征与年龄匹配的正常HDL- c儿童和低HDL- c的CAD患者的HDL- c的风险来评估CAD的风险。对206例血脂异常儿童、65例肥胖儿童、93例低HDL-C （<40 mg/dL）冠心病患者和128例HDL-C正常儿童的血脂和载脂蛋白进行了测定。为了评价HDL的理化特性，对128例HDL- c正常、71例血脂异常、33例肥胖、93例冠心病的儿童进行了血浆胆固醇（MERplasma和FERplasma）和HDL （MERHDL和FERHDL）的摩尔酯化率和分级酯化率的测定。与对照组相比，低HDL- c儿童的脂质和载脂蛋白水平以及HDL的理化特征显示出动脉粥样硬化特征。因此，我们接下来研究了低HDL-C儿童和低HDL-C冠心病患者的脂质和载脂蛋白谱的差异。我们根据HDL-C水平对两组受试者进行了研究（第一组：< 30mg /dL，第二组30l-HDL-C<40mgldL）。与冠心病患者相比，I组儿童显示出更少的致动脉粥样硬化载脂蛋白谱（较低的载脂蛋白ob和较高的载脂蛋白a -I /载脂蛋白ob）。在第二组儿童中也发现了类似的结果，但差异不如第一组儿童明显。低HDL-C患儿的FERHDL与CAD患者相似。这些发现提示，低HDL-C患儿HbL的理化特征与CAD患者相似，但载脂蛋白异常较CAD患者轻微。因此，如果我们能够防止载脂蛋白的性质进一步改变，低HDL-C的儿童在以后的生活中可能不会成为冠心病的高风险。采用PCR-RFLP对D442G和Intl4A基因进行CETP缺失基因分析。从大量筛查的血脂异常儿童的干血斑中提取DNA。营养分析由熊本大学医院临床营养师进行。对181例血脂异常儿童进行CETP基因分析。未发现有Intl4A突变的患儿，但有13例患儿存在D442G突变杂合子。他们的血浆HDL-C、apoA-I和apoA-II水平与没有CETP基因突变的儿童相似。这些结果表明，幼儿CETP缺乏可能不会影响HDL的血浆浓度。可能还需要其他因素来提高血浆中高密度脂蛋白的水平。少

项目成果

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Kawano T: "Inhibitory Effects of HepG2 Cell-derived Apolipoprotein A-I-containing Lipoproteins on Cholesteryl Ester Accumulation in Macrophages." Biochemistry. 36. 9816-9825 (1997)

Kawano T：“HepG2 细胞衍生的载脂蛋白 A-I 含有的脂蛋白对巨噬细胞中胆固醇酯积累的抑制作用。”

Ohta T, Kakiuchi Y, Kuwahara K, Nagata N, Saku K, Takata K, Matsuda I.: "Fractional esterification rate of cholesterol in high density lipoprotein is correlated with low density lipoprotein particle size in children." J Lipid Res. 38. 139-146 (1997)

Ohta T、Kakiuchi Y、Kuwahara K、Nagata N、Saku K、Takata K、Matsuda I.：“高密度脂蛋白中胆固醇的部分酯化率与儿童低密度脂蛋白粒径相关。”

Saku K, Takeda Y, Nii T, Shirai K, Okabe M, Ohta T, Arakawa K.: "Three-dimentional spiral computed tomography angiography as an alternative imaging modality for a silent dissecting aortic aneurysm." Angiology. 48. 1067-1071 (1997)

Saku K、Takeda Y、Nii T、Shirai K、Okabe M、Ohta T、Arakawa K.：“三维螺旋计算机断层扫描血管造影作为无声夹层主动脉瘤的替代成像方式。”

Saku K: "Troglitazone lowers blood pressure and enhances insulin sensitivity in Watanabe heritable" Am J Hypertension. 10. 1027-1033 (1997)

Saku K：“曲格列酮可降低渡边遗传性患者的血压并增强胰岛素敏感性”Am J 高血压。