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)

1.小的低密度脂蛋白（LDL）颗粒被认为比大的LDL颗粒更易致动脉粥样硬化，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。为了帮助预防冠状动脉疾病（CAD），了解儿童和青少年时期的风险因素可能是有用的。在本研究中，我们评价低密度脂蛋白颗粒大小（LDL大小）的梯度凝胶电泳在70名健康儿童（30名男孩和40名女孩）沿着与传统的脂质和脂蛋白参数，被认为是影响LDL大小。测定了血浆和HDL中胆固醇的酯化率和摩尔酯化率（PER和MER）。正如所料，男女的血浆TG、HDL-胆固醇（HDL-C）和apoA-I水平与LDL大小密切相关。然而，发现HDL中的FER（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，FERHDL单独占76%， 关于我们 男孩和女孩中LDL大小的变异性分别为41%。高密度脂蛋白中的MER在男孩和女孩中分别占额外的4%和19%。其他参数，包括血浆TG，HDL-C和apoA-I没有显着的额外影响。因此，FERHDL的测定对预测儿童LDL的颗粒大小是有用的.低血浆E（DL-C）是成人CAD的主要危险因素。在儿科领域，具有低血浆HDL-C的受试者通常在肥胖或血脂异常的儿童中发现。然而，在这方面，目前尚不清楚儿童低HDL-C是否应被视为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及其HDL的理化特征，与年龄匹配的正常HDL-C儿童和低HDL-C的CAD患者进行比较，评估低HDL-C儿童CAD的风险。对206例血脂异常儿童进行血脂及载脂蛋白测定65例肥胖儿童，93例低HDL-C冠心病患者（<40 mg/dL）和128名HDL-C正常儿童。为了评估HDL的理化特征，血浆中胆固醇的摩尔和分数酯化率（MER血浆和FERplasma）和HDL对128例HDL-C正常儿童、71例血脂异常儿童、33例肥胖儿童和93例冠心病儿童进行MERHDL和FERHDL测定，并与对照组比较，低HDL-C儿童的血脂和载脂蛋白水平以及HDL的理化特性均显示出致动脉粥样硬化的特征。因此，我们接下来研究了低HOL-C儿童和低HDL-C CAD患者的血脂和载脂蛋白谱的差异。我们研究了两组受试者的HDL-C水平，（组I：<30mg/dL，组II 301-HDL-C <40mg/dL）。与CAD相比，I组儿童显示较少的致动脉粥样硬化载脂蛋白谱（较低的apoB和较高的apoA-I/apoB比值）。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突出。低HDL-C患儿FERHDL与CAD患儿相似，提示低HDL-C患儿HbL的理化特征与CAD相似，但载脂蛋白B的异常较CAD患儿轻。因此，如果我们能够阻止载脂蛋白B的性质进一步改变，低HDL-C儿童可能不会成为CAD的高风险在以后的生活中。3.采用PCR-RFLP技术对D442 G和Int 14 A进行CETP缺陷基因分析。营养分析由熊本大学医院的临床营养师进行。对181例血脂异常儿童进行CETP基因分析。未发现Int 14 A突变，但发现13例D442 G突变杂合子。其血浆HDL-C、apoA-I、apoA-II水平与CETP基因无突变儿童相似。提示CETP缺乏可能不影响血浆HDL水平，可能需要其他因素的影响才能使血浆HDL水平升高。少

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