Arteriosclerosis, Thrombosis, and Vascular Biology. 1998;18:1723-1729
© 1998 American Heart Association, Inc.
Original Contributions |
Common Variants in the Promoter of the Hepatic Lipase Gene Are Associated With Lower Levels of Hepatic Lipase Activity, Buoyant LDL, and Higher HDL2 Cholesterol
From the Division of Metabolism, Endocrinology, and Nutrition, Department of Medicine (A.Z., J.E.H., J.D.B.), the Division of Medical Genetics, Department of Genetics (S.S.D.), and the Division of Cardiology, Department of Medicine (B.G.B.), University of Washington, Seattle.
Correspondence to Dr John D. Brunzell, University of Washington, Department of Medicine, Division of Metabolism, Endocrinology and Nutrition, 1959 NE Pacific St, Box 356178, Seattle, WA 98195-6178.
Abstract—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.
Key Words: LDL • HDL • triglycerides • cardiovascular disease • lipoprotein lipase
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