A promoter polymorphism in cholesterol 7α-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 7α-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 10 mg. 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), ɛ2 or ɛ4. 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.