Common variants of HMGCR, CETP, APOAI, ABCB1, CYP3A4, and CYP7A1 genes as predictors of lipid-lowering response to atorvastatin therapy

DNA Cell Biol. 2010 Oct;29(10):629-37. doi: 10.1089/dna.2009.1008.

Abstract

There is interindividual variation in lipid-lowering response to statins. The objective of this study was to investigate whether common variation in genes involved in lipid and statin metabolism modify the effect of statins on serum total cholesterol (TC), low-density lipoprotein-cholesterol (LDL-C), and high-density lipoprotein-cholesterol concentration in coronary artery disease (CAD) patients. We studied the association between 18 single-nucleotide polymorphisms (SNPs) in six genes (HMGCR, CETP, APOAI, ABCB1, CYP3A4, CYP7A1) in response to atorvastatin therapy (20 mg/day) in 265 newly diagnosed CAD patients using multivariable adjusted general linear regression. Variant alleles of ABCB1 (-41A/G), HMGCR SNP29 G/T, rs5908A/G, rs12916C/T, and CYP7A1-204A/C polymorphisms were significantly associated with attenuated LDL-C reduction and variant alleles of CETP TaqI, -629C/A, and APOAI PstI polymorphisms were associated with higher increase in high-density lipoprotein-cholesterol. A three-loci interaction model consisting of CYP7A1rs892871AA/APOAIPstIP1P1/HMGCR rs12916CT was a better predictor for LDL-C lowering, when compared with single polymorphisms analysis on statin response. Variant genotypes of APOAI -2500C/T, CETP 405I/V, and ABCB1 3435C/T showed higher risk of myocardial infarction events (p < 0.05) in a 1-year follow-up of CAD patients. These results suggest that SNPs in lipid and statin pathway genes are associated with reduced LDL-C lowering by statins and identify individuals who may be resistant to maximal LDL-C lowering by statins.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / genetics*
  • Adult
  • Alleles*
  • Apolipoprotein A-I / genetics*
  • Atorvastatin
  • Cholesterol 7-alpha-Hydroxylase
  • Cholesterol Ester Transfer Proteins / genetics
  • Cholesterol, HDL / blood
  • Cholesterol, HDL / genetics
  • Cholesterol, LDL / blood
  • Cholesterol, LDL / drug effects
  • Cholesterol, LDL / genetics
  • Coronary Artery Disease / genetics
  • Cytochrome P-450 CYP3A / genetics*
  • Cytochrome P-450 Enzyme System / genetics
  • Female
  • Genotype
  • Heptanoic Acids / therapeutic use*
  • Humans
  • Hydroxymethylglutaryl CoA Reductases
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors / therapeutic use*
  • Lipids / blood*
  • Lipids / genetics
  • Male
  • Middle Aged
  • Myocardial Infarction / genetics
  • Polymorphism, Single Nucleotide*
  • Pyrroles / therapeutic use*
  • Triglycerides / blood

Substances

  • ABCB1 protein, human
  • ATP Binding Cassette Transporter, Subfamily B
  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Apolipoprotein A-I
  • CETP protein, human
  • Cholesterol Ester Transfer Proteins
  • Cholesterol, HDL
  • Cholesterol, LDL
  • Heptanoic Acids
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors
  • Lipids
  • Pyrroles
  • Triglycerides
  • Cytochrome P-450 Enzyme System
  • Atorvastatin
  • HMGCR protein, human
  • Hydroxymethylglutaryl CoA Reductases
  • Cytochrome P-450 CYP3A
  • CYP7A1 protein, human
  • Cholesterol 7-alpha-Hydroxylase
  • CYP3A4 protein, human