Hovingh G Kees, Hutten Barbara A, Holleboom Adriaan G, Petersen Wilma, Rol Patrick, Stalenhoef Anton, Zwinderman Aeilko H, de Groot Eric, Kastelein John J P, Kuivenhoven Jan Albert
Department of Vascular Medicine, Academic Medical Center, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands.
Circulation. 2005 Aug 9;112(6):879-84. doi: 10.1161/CIRCULATIONAHA.105.540427. Epub 2005 Aug 1.
Prospective epidemiological studies have shown that low plasma levels of HDL cholesterol (HDL-C) are associated with an increased risk for cardiovascular disease (CVD). Despite nearly 40 years of research, however, it is unclear whether this also holds true for individuals with severely reduced levels of HDL-C due to mutations in the lecithin:cholesterol acyltransferase (LCAT) gene. Better insight into CVD risk in these individuals may provide clues toward the potential of LCAT as a pharmaceutical target to raise HDL-C levels.
Lipids, lipoproteins, high-sensitivity C-reactive protein (CRP), and carotid artery intima-media thickness (IMT) were assessed in 47 heterozygotes for LCAT gene mutations and 58 family controls. Compared with controls, heterozygotes presented with a mean 36% decrease in HDL-C levels (P<0.0001), a 23% increase in triglyceride levels (P<0.0001), and a 2.1-fold increase in CRP levels (P<0.0001). Mean carotid IMT was significantly increased in heterozygotes compared with family controls (0.623+/-0.13 versus 0.591+/-0.08 mm). After adjustment for age, gender, and alcohol use, this difference proved statistically significant (P<0.0015).
The data show that heterozygosity for LCAT gene defects is associated with low HDL-C levels and elevated concentration of triglycerides and CRP in plasma. This phenotype underlies increased IMT in carriers versus controls, which suggests that LCAT protects against atherosclerosis. This in turn indicates that targeting LCAT to raise HDL-C may reduce CVD risk.
前瞻性流行病学研究表明，血浆高密度脂蛋白胆固醇（HDL-C）水平低与心血管疾病（CVD）风险增加相关。然而，尽管经过近40年的研究，尚不清楚对于因卵磷脂胆固醇酰基转移酶（LCAT）基因突变导致HDL-C水平严重降低的个体是否也是如此。深入了解这些个体的CVD风险可能为将LCAT作为提高HDL-C水平的药物靶点的潜力提供线索。
对47名LCAT基因突变杂合子和58名家族对照者进行了血脂、脂蛋白、高敏C反应蛋白（CRP）和颈动脉内膜中层厚度（IMT）评估。与对照组相比，杂合子的HDL-C水平平均降低36%（P<0.0001），甘油三酯水平升高23%（P<0.0001），CRP水平升高2.1倍（P<0.0001）。与家族对照者相比，杂合子的平均颈动脉IMT显著增加（0.623±0.13对0.591±0.08mm）。在对年龄、性别和饮酒情况进行校正后，这种差异具有统计学意义（P<0.0015）。
数据表明，LCAT基因缺陷杂合性与HDL-C水平低、血浆甘油三酯和CRP浓度升高相关。这种表型是携带者与对照组IMT增加的基础，这表明LCAT可预防动脉粥样硬化。这反过来表明，靶向LCAT以提高HDL-C可能降低CVD风险。
