title: Common hepatic lipase gene promoter variant determines clinical response to intensive lipid-lowering treatment.
abstract: 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.
  
  
  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.affiliation: Department of Medicine, University of Washington, Seattle, WA 98195-6426, USA. brunzell@u.washington.edu
authors.forename: A
authors.initials: A
authors.lastname: Zambon
authors.forename: S S
authors.initials: SS
authors.lastname: Deeb
authors.forename: B G
authors.initials: BG
authors.lastname: Brown
authors.forename: J E
authors.initials: JE
authors.lastname: Hokanson
authors.forename: J D
authors.initials: JD
authors.lastname: Brunzell
mesh_terms: D000704:Analysis of Variance; D008076:Cholesterol, HDL / Q000097:blood; D003084:Colestipol / Q000627:therapeutic use; D017023:Coronary Angiography; D003327:Coronary Disease / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism; D004359:Drug Therapy, Combination; D005838:Genotype; D006801:Humans; D006949:Hyperlipidemias / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism; D000960:Hypolipidemic Agents / Q000627:therapeutic use*; D008049:Lipase / Q000037:antagonists & inhibitors* / Q000097:blood / Q000235:genetics; D008075:Lipoproteins, HDL / Q000378:metabolism; D008077:Lipoproteins, LDL / Q000378:metabolism; D008099:Liver / Q000201:enzymology*; D008148:Lovastatin / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D009525:Niacin / Q000627:therapeutic use; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D011379:Prognosis; D011401:Promoter Regions, Genetic; D012044:Regression Analysis
chemical_list: D008076:Cholesterol, HDL; D000960:Hypolipidemic Agents; D008075:Lipoproteins, HDL; D008077:Lipoproteins, LDL; D009525:Niacin; D008148:Lovastatin; D008049:Lipase; D003084:Colestipol