A promoter polymorphism in cholesterol 7alpha-hydroxylase interacts with apolipoprotein E genotype in the LDL-lowering response to atorvastatin.
Bile-acid biosynthesis is a key determinant of intracellular cholesterol and, in turn, cholesterol synthesis rate in hepatocytes. This suggests that variation in the cholesterol 7alpha-hydroxylase gene (CYP7A1), a key enzyme in bile-acid biosynthesis, may influence the statin response. To test this hypothesis, a promoter polymorphism (A-204C) in CYP7A1 was examined in 324 hypercholesterolemic patients treated with atorvastatin 10mg. The variant C allele was significantly and independently associated with poor LDL cholesterol reductions; -39% in wild type allele homozygotes, -37% in variant allele heterozygotes, and -34% in variant allele homozygotes (p<0.0001 for trend). Differences were more striking in men, and were enhanced by the coexistence of common variants of apolipoprotein E gene (APOE), epsilon2 or epsilon4. In subjects having wild type alleles at both loci, the mean reduction in LDL cholesterol was -40%, while the value in subjects having two CYP7A1 variant alleles and at least one variant APOE allele was -31% (p<0.0001). Combination analysis of these two loci more accurately predicted the achievement of goal LDL cholesterol, than did both single locus analysis. We concluded that the CYP7A1 A-204C promoter variant was associated with poor response to atorvastatin, which were additively enhanced by common variants in another locus, APOE.
Kajinami
Kouji
K
Lipid Research Laboratory, Division of Endocrinology Metabolism and Molecular Biology, Tufts-New England Medical Center, Boston, USA. kajinami@kanazawa-med.ac.jp
Brousseau
Margaret E
ME
Ordovas
Jose M
JM
Schaefer
Ernst J
EJ
D000368:Aged; D000924:Anticholesteremic Agents / Q000494:pharmacology* / Q000627:therapeutic use*; D001057:Apolipoproteins E / Q000235:genetics*; D000069059:Atorvastatin; D001647:Bile Acids and Salts / Q000096:biosynthesis; D002790:Cholesterol 7-alpha-Hydroxylase / Q000235:genetics* / Q000378:metabolism*; D008078:Cholesterol, LDL / Q000097:blood / Q000187:drug effects; D004311:Double-Blind Method; D005260:Female; D005838:Genotype; D006538:Heptanoic Acids / Q000494:pharmacology* / Q000627:therapeutic use*; D006801:Humans; D006937:Hypercholesterolemia / Q000188:drug therapy; D008148:Lovastatin / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D010919:Placebos; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic / Q000235:genetics; D011758:Pyrroles / Q000494:pharmacology* / Q000627:therapeutic use*; D012737:Sex Factors; D016896:Treatment Outcome
D000924:Anticholesteremic Agents; D001057:Apolipoproteins E; D001647:Bile Acids and Salts; D008078:Cholesterol, LDL; D006538:Heptanoic Acids; D010919:Placebos; D011758:Pyrroles; D008148:Lovastatin; D000069059:Atorvastatin; D002790:Cholesterol 7-alpha-Hydroxylase