Zambon A, Deeb S S, Hokanson J E, Brown B G, Brunzell J D
Division of Metabolism, Endocrinology, and Nutrition, Department of Medicine, University of Washington, Seattle, USA.
Arterioscler Thromb Vasc Biol. 1998 Nov;18(11):1723-9. doi: 10.1161/01.atv.18.11.1723.
Increased hepatic lipase (HL) activity is associated with small, dense, low density lipoprotein (LDL) and low high density lipoprotein2 (HDL2) cholesterol (-C) levels. A polymorphism in the promoter region of the HL gene (LIPC) is associated with HDL-C levels. To test whether this association is mediated by differences in HL activity between different LIPC promoter genotypes, the LIPC promoter polymorphism at position -250 (G-->A), HL activity, LDL buoyancy, and HDL-C levels were studied in white normolipidemic men and men with coronary artery disease (CAD). The less common A allele (frequency=0.21 and 0.25 in normal and CAD subjects, respectively) was associated with lower HL activity (P<0.005 by ANOVA) and buoyant LDL particles (P</=0.01) in both groups. Normal and CAD subjects heterozygous for the A allele had lower HL activity (by 24% and 29%, respectively) and significantly more buoyant LDL particles. Homozygosity for this allele (AA) was associated with an even lower HL activity in normal (-26%) and CAD (-46%) subjects. The A allele was associated with higher HDL2-C in CAD patients (P=0.007); heterozygotes and homozygotes for the A allele had a 92% and a 140% higher HDL2-C level (P<0.01) than did GG individuals. In a small number of normolipidemic subjects, the same trend in HDL2-C was seen. In a univariate analysis, the LIPC genotype accounted for 20% to 32% of the variance in HL levels among normal subjects and CAD patients, respectively. After adjustment for HL, the association between LIPC genotype and LDL buoyancy was no longer significant, suggesting that the effect of LIPC genotype on LDL buoyancy is mediated by its effects on HL activity. The LIPC A allele was more frequent in Japanese-Americans and African-Americans than in whites. In summary, these results suggest that variants in the LIPC promoter may significantly contribute to the variance in levels of HL activity and consequently, to the prevalence of the atherogenic small, dense, LDL particles and low HDL2-C levels.
肝脂酶（HL）活性增加与小而密的低密度脂蛋白（LDL）以及低高密度脂蛋白2（HDL2）胆固醇（-C）水平相关。HL基因（LIPC）启动子区域的多态性与HDL-C水平相关。为了检验这种关联是否由不同LIPC启动子基因型之间HL活性的差异介导，我们在血脂正常的白人男性和患有冠状动脉疾病（CAD）的男性中研究了位于-250位置的LIPC启动子多态性（G→A）、HL活性、LDL浮力和HDL-C水平。较罕见的A等位基因（在正常和CAD受试者中的频率分别为0.21和0.25）与两组中较低的HL活性（方差分析P<0.005）和漂浮的LDL颗粒（P≤0.01）相关。A等位基因杂合的正常和CAD受试者HL活性较低（分别降低24%和29%），且漂浮的LDL颗粒显著更多。该等位基因的纯合子（AA）在正常（-26%）和CAD（-46%）受试者中与更低的HL活性相关。A等位基因与CAD患者中更高的HDL2-C相关（P=0.007）；A等位基因的杂合子和纯合子的HDL2-C水平比GG个体分别高92%和140%（P<0.01）。在少数血脂正常的受试者中也观察到了HDL2-C的相同趋势。在单变量分析中，LIPC基因型分别占正常受试者和CAD患者中HL水平变异的20%至32%。在对HL进行校正后，LIPC基因型与LDL浮力之间的关联不再显著，这表明LIPC基因型对LDL浮力的影响是由其对HL活性的影响介导的。LIPC A等位基因在日裔美国人和非裔美国人中比在白人中更常见。总之，这些结果表明，LIPC启动子中的变异可能显著导致HL活性水平的差异，进而导致致动脉粥样硬化的小而密LDL颗粒的流行率和低HDL2-C水平。
