BACKGROUND: The common -514C-->T 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 HDL(2) 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 (14)C-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 C:C 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 HDL(2)-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 -514C-->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.
RCT Entities:
BACKGROUND: The common -514 C-->T 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 HDL(2) 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 (14)C-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 C:C 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 HDL(2)-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.
Authors: B D Horne; J L Anderson; J F Carlquist; J B Muhlestein; D G Renlund; T L Bair; R R Pearson; N J Camp Journal: Ann Hum Genet Date: 2005-03 Impact factor: 1.670
Authors: Tina E Brinkley; Amy Halverstadt; Dana A Phares; Robert E Ferrell; Ronald L Prigeon; James M Hagberg; Andrew P Goldberg Journal: J Appl Physiol (1985) Date: 2011-09-29
Authors: Alvaro Pulchinelli; Ana Maria Massad Costa; Cristina V de Carvalho; Naiara Correa Nogueira de Souza; Mauro A Haidar; Adagmar Andriolo; Ismael D C Guerreiro da Silva Journal: Lipids Health Dis Date: 2011-11-02 Impact factor: 3.876
Authors: Gualberto Ruaño; Paul D Thompson; John P Kane; Clive R Pullinger; Andreas Windemuth; Richard L Seip; Mohan Kocherla; Theodore R Holford; Alan H B Wu Journal: Pharmacogenomics Date: 2010-07 Impact factor: 2.533