Identification of pharmacogenetic predictors of lipid-lowering response to atorvastatin in Chilean subjects with hypercholesterolemia.

BACKGROUND: Statins are normally the first-line therapy for hypercholesterolemia (HC); however, the lipid-lowering response shows high interindividual variation. We investigated the effect of four polymorphisms in CYP3A4, CYP3A5 and ABCB1 genes on response to atorvastatin and CYP3A4 activity in Chilean subjects with HC. METHODS: A total of 142 hypercholesterolemic individuals underwent atorvastatin therapy (10mg/day/1month). Serum lipid levels before and after treatment were measured. Genetic variants in CYP3A4 (-290A>G, rs2740574), CYP3A5 (6986A>G, rs776746) and ABCB1 (2677G>A/T, rs2032582 and 3435C>T, rs1045642) were analyzed by PCR-RFLP. CYP3A4 enzyme activity in urine samples was assessed through determination of 6ß-hydroxycortisol/cortisol free ratio (6ßOHC/FC). RESULTS: After 4weeks of therapy, a significant reduction in total cholesterol (TC) and LDL-c was observed (P<0.001). The G allele for -290A>G polymorphism was related to higher percentage of variation in TC and LDL-c (P<0.001). Moreover, same allele was associated with higher HDL-c variation (P=0.017). In addition, CYP3A4 enzyme activity was lower in subjects carrying this polymorphism (P=0.009). No differences were observed for CYP3A5 and ABCB1 variants. CONCLUSION: Our results suggest that presence of G allele for -290A>G polymorphism determines a better response to atorvastatin, being also associated with lower CYP3A4 activity in vivo, causing an increased atorvastatin activity.