Pharmacogenetic Predictors of Statin-Mediated Low-Density Lipoprotein Cholesterol Reduction and Dose Response

Background-There is interindividual variation in low-density lipoprotein cholesterol (LDLc) lowering by statins and limited study into the genetic associations of the dose dependant LDLc lowering by statins. Methods and Results-Five hundred nine patients with hyperlipidemia were randomly assigned atorvastatin 10 mg, simvastatin 20 mg, or pravastatin 10 mg (low-dose phase) followed by 80 mg, 80 mg, and 40 mg (high-dose phase), respectively. Thirty-one genes in statin, cholesterol, and lipoprotein metabolism were sequenced and 489 single nucleotide polymorphisms with minor allele frequencies > 2% were tested for associations with percentage LDLc lowering at low doses using multivariable adjusted general linear regression. Significant associations from the analysis at low dose were then repeated at high-dose statins. At low doses, only 1 single nucleotide polymorphism met our experiment-wide significance level, ABCA1 rs12003906. Twenty-six subjects carried the minor allele of rs12003906, which was associated with an attenuated LDLc reduction (LDLc reduction in carriers versus noncarriers - 24.1 +/- 2.6% versus - 32.2 +/- 1.5%; P = 0.0001). In addition, we replicated the association with the APOE epsilon 3 allele and a reduced LDLc reduction. At high doses, carriers of the minor allele of ABCA1 rs12003906 and the APOE epsilon 3 allele improved their LDLc reduction but continued to have a diminished LDLc reduction compared with noncarriers (- 30.5 +/- 4.0% versus - 42.0 +/- 2.4%; P = 0.005) and (- 38.5 +/- 1.9% versus - 45.3 +/- 2.8%; P = 0.009), respectively. Conclusions-An intronic single nucleotide polymorphism in ABCA1 and the APOE epsilon 3 allele are associated with reduced LDLc lowering by statins and identify individuals who may be resistant to maximal LDLc lowering by statins. (Circ Cardiovasc Genet. 2008;1:100-106.)