Hepatic metabolism and transporter gene variants enhance response to rosuvastatin in patients with acute myocardial infarction: the GEOSTAT-1 Study.

Background —Pharmacogenetics aims to maximize benefits and minimize risks of drug treatment. Our objectives were to examine the influence of common variants of hepatic metabolism and transporter genes on the lipid-lowering response to statin therapy. Methods and Results —GEOSTAT-1 was a genetic sub-study of SPACE ROCKET (a randomized controlled trial comparing simvastatin 40mg and rosuvastatin 10mg) recruiting 601 patients following myocardial infarction. We genotyped the following functional single nucleotide polymorphisms (SNPs) in the genes encoding for the cytochrome P450 metabolic enzymes, CYP2C9*2 (430C>T), CYP2C9*3 (1075A>C), CYP2C19*2 (681G>A), CYP3A5*1 (6986A>G) and hepatic influx and efflux transporters, SLCO1B1 (521T>C) and BCRP (421C>A). We assessed 3-month low-density-lipoprotein cholesterol (LDL-C) levels and the proportion of patients reaching the current LDL-C target of <70mg/dL (<1.81mmol/L). An enhanced response to rosuvastatin was seen for patients with variant genotypes of either CYP3A5 (p=0.006) or BCRP (p=0.010). Furthermore, multivariate logistic regression analysis revealed patients with at least one variant CYP3A5 and/or BCRP allele (n=186) were more likely to achieve the LDL-C target (OR: 2.289; 95% CI: 1.157, 4.527; p=0.017; rosuvastatin 54.0% to target v. simvastatin 33.7%). There were no differences for patients with variants of CYP2C9, CYP2C19 or SLCO1B1, in comparison to their respective wild-types, nor were differential effects on statin response seen for patients with the most common genotypes for CYP3A5 and BCRP (n=415; OR: 1.207; 95% CI: 0.768, 1.899; p=0.415). Conclusion —The LDL-C target was achieved more frequently for the one-in-three patients with CYP3A5 and/or BCRP variant genotypes when prescribed rosuvastatin 10mg, compared to simvastatin 40mg. Clinical Trial Registration Information —http://isrctn.org; ISRCTN 89508434