Hirano K, Yamashita S, Nakajima N, Arai T, Maruyama T, Yoshida Y, Ishigami M, Sakai N, Kameda-Takemura K, Matsuzawa Y
Second Department of Internal Medicine, Osaka University Medical School, Japan.
Arterioscler Thromb Vasc Biol. 1997 Jun;17(6):1053-9. doi: 10.1161/01.atv.17.6.1053.
Low levels of HDL cholesterol have been clearly demonstrated to be associated with an increased incidence of coronary heart disease, strongly suggesting that HDL particles have an antiatherogenic function. However, little information has been available concerning the atherogenicity of a marked hyperalphalipoproteinemia (HALP). There is no agreement about whether plasma cholesteryl ester transfer protein (CETP) deficiency is associated with an antiatherogenic state or not, although this disorder was reported to be one of the major causes of marked HALP. In the current study, we have found a unique area (Omagari City, Akita Prefecture, Japan) where CETP deficiency caused by a G-to-A mutation at the 5' splice donor site of intron 14 in the CETP gene is extremely frequent. In Omagari City, the mutation was detected more than 20 times more frequently and the prevalence of a marked HALP with plasma HDL cholesterol > or = 2.58 mmol/L (100 mg/dL) was 5 to 10 times higher than in other areas of Japan. This discovery has made it possible to perform a large population-based study concerning the atherogenicity of a marked elevation of HDL cholesterol in a genetically more homogeneous population. There was a statistically significant U-shaped relationship between HDL cholesterol levels and the incidence of ischemic changes in electrocardiograms. In cases of HDL cholesterol < 1.81 mmol/L (70 mg/dL), the incidence increased in proportion to the levels of HDL cholesterol. The frequency of the CETP gene mutation was higher in patients with coronary heart disease than in healthy control subjects. In subjects aged > 80 years, the prevalence of both marked HALP and the intron 14 splicing defect was significantly lower than in the younger generation. The current study indicated for the first time that a marked HALP caused by CETP gene mutation may not represent a longevity syndrome, suggesting the importance of reevaluation of the clinical significance and pathophysiology of a marked HALP.
低水平的高密度脂蛋白胆固醇（HDL胆固醇）已被明确证明与冠心病发病率增加有关，这强烈表明HDL颗粒具有抗动脉粥样硬化功能。然而，关于显著高α脂蛋白血症（HALP）的动脉粥样硬化性，几乎没有可用信息。关于血浆胆固醇酯转运蛋白（CETP）缺乏是否与抗动脉粥样硬化状态相关，目前尚无定论，尽管这种疾病据报道是显著HALP的主要原因之一。在本研究中，我们发现了一个独特的地区（日本秋田县大曲市），其中由CETP基因第14内含子5'剪接供体位点的G到A突变导致的CETP缺乏极为常见。在大曲市，该突变的检测频率比其他地区高出20倍以上，且血浆HDL胆固醇≥2.58 mmol/L（100 mg/dL）的显著HALP患病率比日本其他地区高5至10倍。这一发现使得在基因上更同质的人群中进行关于HDL胆固醇显著升高的动脉粥样硬化性的大规模人群研究成为可能。HDL胆固醇水平与心电图缺血性改变的发生率之间存在统计学上显著的U形关系。在HDL胆固醇<1.81 mmol/L（70 mg/dL）的情况下，发生率与HDL胆固醇水平成比例增加。冠心病患者中CETP基因突变的频率高于健康对照受试者。在年龄>80岁的受试者中，显著HALP和第14内含子剪接缺陷的患病率均显著低于年轻一代。本研究首次表明，由CETP基因突变引起的显著HALP可能并不代表长寿综合征，这表明重新评估显著HALP的临床意义和病理生理学的重要性。
