title: Common C-to-T substitution at position -480 of the hepatic lipase promoter associated with a lowered lipase activity in coronary artery disease patients.
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.
authors.affiliation: Department of Internal Medicine, Erasmus University Rotterdam, The Netherlands. jansen@bcl.fgg.eur.nl
authors.forename: H
authors.initials: H
authors.lastname: Jansen
authors.forename: A J
authors.initials: AJ
authors.lastname: Verhoeven
authors.forename: L
authors.initials: L
authors.lastname: Weeks
authors.forename: J J
authors.initials: JJ
authors.lastname: Kastelein
authors.forename: D J
authors.initials: DJ
authors.lastname: Halley
authors.forename: A
authors.initials: A
authors.lastname: van den Ouweland
authors.forename: J W
authors.initials: JW
authors.lastname: Jukema
authors.forename: J C
authors.initials: JC
authors.lastname: Seidell
authors.forename: J C
authors.initials: JC
authors.lastname: Birkenhäger
mesh_terms: D000483:Alleles; D003062:Codon / Q000235:genetics; D003327:Coronary Disease / Q000201:enzymology* / Q000235:genetics; D005091:Exons / Q000235:genetics; D005820:Genetic Testing; D005838:Genotype; D006801:Humans; D007328:Insulin / Q000097:blood; D008049:Lipase / Q000097:blood / Q000235:genetics*; D008055:Lipids / Q000097:blood; D008071:Lipoprotein Lipase / Q000097:blood; D008099:Liver / Q000201:enzymology*; D008297:Male; D008875:Middle Aged; D017354:Point Mutation; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic / Q000235:genetics*
chemical_list: D003062:Codon; D007328:Insulin; D008055:Lipids; D008049:Lipase; D008071:Lipoprotein Lipase