Common Variants in the Promoter of the Hepatic Lipase Gene Are Associated With Lower Levels of Hepatic Lipase Activity, Buoyant LDL, and Higher HDL 2 Cholesterol

Abstract

Abstract —Increased hepatic lipase (HL) activity is associated with small, dense, low density lipoprotein (LDL) and low high density lipoprotein 2 (HDL 2 ) 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 HDL 2 -C in CAD patients ( P =0.007); heterozygotes and homozygotes for the A allele had a 92% and a 140% higher HDL 2 -C level ( P <0.01) than did GG individuals. In a small number of normolipidemic subjects, the same trend in HDL 2 -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 HDL 2 -C levels.