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

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.