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(Circulation. 2001;103:792.)
© 2001 American Heart Association, Inc.

Clinical Investigation and Reports

Common Hepatic Lipase Gene Promoter Variant Determines Clinical Response to Intensive Lipid-Lowering Treatment

Alberto Zambon, MD, PhD; Samir S. Deeb, PhD; B. Greg Brown, MD, PhD; John E. Hokanson, PhD; John D. Brunzell, MD

From the Department of Medicine, University of Washington, Seattle.

Correspondence to John D. Brunzell, MD, University of Washington, Department of Medicine, 1959 NE Pacific St, Box 356426, Seattle, WA 98195-6426. E-mail brunzell{at}u.washington.edu

Background—The common -514 CT polymorphism in the promoter region of the hepatic lipase (HL) gene affects HL activity. The C allele is associated with higher HL activity, more dense and atherogenic LDL, and lower HDL₂ cholesterol. Intensive lipid-lowering therapy lowers HL activity, increases LDL and HDL buoyancy, and promotes coronary artery disease (CAD) regression. We tested the hypothesis that subjects with the CC genotype and a more atherogenic lipid profile experience the greatest CAD regression from these favorable effects.

Methods and Results—Forty-nine middle-aged men with dyslipidemia and established CAD who were undergoing intensive lipid-lowering therapy were studied. Change in coronary stenosis was assessed by quantitative angiography, HL polymorphism by polymerase chain reaction amplification, HL activity by ¹⁴C-labeled substrate, and LDL buoyancy by density-gradient ultracentrifugation. The response to lipid-lowering therapy was significantly different among subjects with different HL promoter genotypes. Subjects with the CC genotype had the greatest decrease in HL activity (P<0.005 versus TC and TT by ANOVA) and the greatest improvement in LDL density (P<0.005) and HDL₂-C (P<0.05) with therapy. These subjects had the greatest angiographic improvement, with 96% of them experiencing CAD regression, compared with 60% of TC and none of the TT patients (P<0.001).

Conclusions—In middle-aged men with established CAD and dyslipidemia, the HL gene -514 CT polymorphism significantly predicts changes in coronary stenosis with lipid-lowering treatment that appear to involve an HL-associated effect on LDL metabolism. This study identifies a gene polymorphism that strongly influences the lipid and clinical response to lipid-lowering drugs.

Key Words: coronary artery disease • liver • genes • lipoproteins • pharmacogenetics

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