Abstract 3447: The Breast Cancer Resistance Protein (BCRP) 421C> A Single Nucleotide Polymorphism Predicts Improved Low-Density-Lipoprotein Cholesterol Reduction by Rosuvastatin
Genetic differences in hepatic transporters may alter the concentration of hydrophilic statins at their site of action within hepatocytes, influencing clinical efficacy. Breast cancer resistance protein (BCRP) and organic anion transporter polypeptide 1B1 (SLCO1B1) are known to transport rosuvastatin. To investigate whether single nucleotide polymorphisms (SNPs) in these genes affect low-density-lipoprotein cholesterol (LDL-C) lowering response to rosuvastatin. Acute coronary syndrome (ACS) patients (n=630) randomly received either 10 mg rosuvastatin or 40 mg simvastatin daily for 3 months. LDL-C was measured during hospital admission and after 3 months treatment. Patients were genotyped for the BCRP 421C>A and SLCO1B1 521T>C SNPs. Differences in mean 3-month LDL-C levels were assessed using independent-samples t-tests. Logistic regression was employed to determine the role of randomised statin in achievement of the current ACC/AHA LDL-C target (<1.81 mmol/l) in each genotyped group. When randomised to rosuvastatin, carriers of one or two variant BCRP A alleles (n=75) achieved significantly lower mean 3-month LDL-C levels than wild-type homozygous individuals (421CC, n=249; 1.78 vs 1.98 mmol/l; p=0.012) and SLCO1B1 wild-type homozygous individuals (521TT, n=241) demonstrated a non-significant trend towards lower mean 3-month LDL-C levels than variant allele carriers (n=83; 1.90 vs 2.01; p=0.148). Neither SNP influenced response amongst patients receiving the lipophilic statin, simvastatin (p=0.720 and p=0.793, respectively). Finally, patients with a variant BCRP allele were 2.8 times more likely to achieve the current ACC/AHA LDL-C target when randomised to 10 mg rosuvastatin compared to 40 mg simvastatin (95% CI = 1.29 to 6.22; p=0.010). The BCRP 421C>A SNP predicts increased cholesterol-lowering response to rosuvastatin. Decreased efflux of rosuv-astatin from hepatocytes, leading to increased concentration at the site of action, is proposed as the mechanism. Clinically, genotyping for the BCRP 421C>A SNP identifies which ACS patients are more likely to achieve the current ACC/AHA LDL-C target when prescribed 10 mg rosuvastatin compared to 40 mg simvastatin.