Arteriosclerosis, Thrombosis, and Vascular Biology. 1997;17:2837-2842
© 1997 American Heart Association, Inc.
Articles |
Common C-to-T Substitution at Position -480 of the Hepatic Lipase Promoter Associated With a Lowered Lipase Activity in Coronary Artery Disease Patients
From the Departments of Internal Medicine III (H.J., L.W., J.C.B.), Biochemistry (H.J., A.J.M.V.), and Clinical Genetics (D.J.J.H., A. van den O.), Erasmus University Rotterdam; the Department of Molecular Medicine, Academic Medical Center, University of Amsterdam (J.J.P.K.); the Department of Cardiology, University of Leiden (J.W.J.); and the Department of Chronic Diseases and Environmental Epidemiology, National Institute of Public Health and Environmental Protection, Bilthoven (J.C.S.), The Netherlands.
Correspondence to Hans Jansen, PhD, Department of Internal Medicine III, BD 277, Erasmus University Rotterdam, Dr Molewaterplein 50, 3015 GD Rotterdam, POB 1738, 3000 DR Rotterdam, The Netherlands. E-mail jansen{at}bc1.fgg.eur.nl
Abstract We studied the molecular basis of low hepatic lipase (HL) activity in normolipidemic male patients with angiographically documented coronary artery disease (CAD). In 18 subjects with a lowered HL activity (<225 mU/mL), all nine exons of the HL gene and part of the promoter region (nucleotides -524 to +7) were sequenced. No structural mutations in the coding part of the HL gene were found, but 50% of the subjects showed a C-to-T substitution at nucleotide -480. Screening for the base substitution in 782 patients yielded an allele frequency of 0.213 (297 heterozygotes, 18 homozygotes). In a group of 316 nonsymptomatic control subjects, the allele frequency was 0.189, which is significantly less than in the CAD patients (P=.035). In the CAD patients, the C-to-T substitution was associated with a lowered lipase activity (heterozygotes -15%, homozygotes -20%). The patients were divided into quartiles on the basis of HL activity. Sixty percent (allele frequency 0.32) of the patients in the lowest quartile (HL activity <306 mU/mL) had the gene variant against 27% (allele frequency 0.14) in the highest quartile (HL activity >466 mU/mL). In the noncarriers, but not in the carriers, HL activity was related with plasma insulin, being increased at higher insulin concentration. Homozygous carriers had a significantly higher HDL cholesterol level than noncarriers (1.13±0.28 mmol/L versus 0.92±0.22 mmol/L, P<.02). Our results show that a C-to-T substitution at -480 of the HL promoter is associated with a lowered HL activity. The base substitution, or a closely linked gene variation, may contribute to the variation in HL activity and affect plasma lipoprotein metabolism.
Key Words: hepatic lipase • promoter • polymorphism • deficiency • coronary artery disease
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