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Common hepatic lipase gene promoter variant determines clinical response to intensive lipid-lowering treatment

A Zambon1, S S Deeb, B G Brown

  • 1Department of Medicine, University of Washington, Seattle, WA 98195-6426, USA. brunzell@u.washington.edu

Circulation
|February 15, 2001
PubMed

Insights

Individuals with the CC genotype of the hepatic lipase (HL) gene showed the most significant coronary artery disease (CAD) regression during lipid-lowering therapy, indicating a strong genetic influence on treatment response.

Area of Science:

  • Genetics and Molecular Biology
  • Cardiovascular Medicine
  • Metabolic Disorders

Background:

  • The -514 C-->T polymorphism in the hepatic lipase (HL) gene promoter influences HL activity, LDL particle density, and HDL(2) cholesterol levels.
  • Individuals with the CC genotype typically exhibit higher HL activity, leading to more atherogenic LDL particles.
  • Intensive lipid-lowering therapy is known to reduce HL activity and improve lipoprotein profiles, potentially promoting coronary artery disease (CAD) regression.

Purpose of the Study:

  • To investigate whether individuals with the CC genotype, characterized by a more atherogenic lipid profile, experience enhanced CAD regression in response to intensive lipid-lowering therapy.
  • To determine if the -514 C-->T polymorphism in the HL gene acts as a predictor of clinical outcomes in patients undergoing lipid-lowering treatment.

Main Methods:

  • Quantitative angiography was used to assess changes in coronary stenosis in 49 middle-aged men with dyslipidemia and established CAD undergoing intensive lipid-lowering therapy.
  • Hepatic lipase (HL) gene polymorphism was analyzed using polymerase chain reaction amplification.
  • HL activity was measured using a (14)C-labeled substrate, and LDL (low-density lipoprotein) particle buoyancy was determined by density-gradient ultracentrifugation.

Main Results:

  • Significant differences in response to lipid-lowering therapy were observed among different HL promoter genotypes.
  • Subjects with the CC genotype demonstrated the greatest reduction in HL activity (P<0.005) and the most substantial improvements in LDL density (P<0.005) and HDL(2)-C (P<0.05).
  • Angiographic analysis revealed that 96% of CC genotype subjects experienced CAD regression, compared to 60% of TC and none of the TT genotype subjects (P<0.001).

Conclusions:

  • The -514 C-->T polymorphism in the HL gene is a significant predictor of changes in coronary stenosis in response to lipid-lowering treatment among middle-aged men with CAD and dyslipidemia.
  • These findings suggest an HL-mediated effect on LDL metabolism contributes to the observed clinical benefits.
  • This genetic polymorphism strongly influences both the lipid and clinical responses to lipid-lowering medications.
Abstract

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