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

Background-The common -514 C-->T polymorphism in the promoter region of the hepatic lipase (KL) gene affects HL activity. The C allele is associated with higher HL activity, more dense and atherogenic LDL, and lower HDL, 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 mon 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, ML polymorphism by polymerase chain reaction amplification, HL activity by C-14-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 C-->T 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.