Common C-to-T substitution at position -480 of the hepatic lipase promoter associated with a lowered lipase activity in coronary artery disease patients

H Jansen, A.J. Verhoeven, L Weeks, J.J. Kastelein, D.J.J. Halley, A. van den Ouweland, J Wouter Jukema, J C Seidell, J C Birkenhäger

Research output: Contribution to JournalArticleAcademicpeer-review

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.

Original languageEnglish
Pages (from-to)2837-42
Number of pages6
JournalArteriosclerosis, Thrombosis, and Vascular Biology
Volume17
Issue number11
DOIs
Publication statusPublished - Nov 1997

Keywords

  • Alleles
  • Codon
  • Coronary Disease
  • Exons
  • Genetic Testing
  • Genotype
  • Humans
  • Insulin
  • Lipase
  • Lipids
  • Lipoprotein Lipase
  • Liver
  • Male
  • Middle Aged
  • Point Mutation
  • Polymerase Chain Reaction
  • Polymorphism, Genetic
  • Promoter Regions, Genetic
  • Journal Article
  • Research Support, Non-U.S. Gov't

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