R ESEARCH ARTICLE 10.2217/14622416.9.9.1217 © 2008 Future Medicine Ltd ISSN 1462-2416 Pharmacogenomics (2008) 9(9), 1217–1227 1217 part of Association between a frequent allele of the gene encoding OAT P1B1 and enhanced LDL-lowering response to fluvastatin therapy Philippe Couvert 1,2,3 , Philippe Giral 1,2,4 , Sylvie Dejager 5 , Jessie Gu 6 , Thierry Huby 1,2 , M John Chapman 1,2 , Eric Bruckert 1,2,4 & Alain Carrié 1,2,3† † Author for correspondence 1 INSERM, UMR S551, Dyslipoproteinemia and Atherosclerosis Research Unit, Hôpital de la Pitié, F-75013, Paris, France Tel.:+33 142 177 855 Fax: +33 145 828 198 E-mail: carrie@ chups.jussieu.fr 2 UPMC, Univ Paris 06, UMR S551, F-75013, Paris, France 3 AP-HP, Groupe hospitalier Pitié-Salpêtrière, Service de Biochimie endocrinienne et oncologique, F-75651 Paris cedex 13, France 4 Department of Endocrinology-Metabolism, APHP, Pavillon Benjamin Delessert, Pitié-Salpêtrière Hospital, 83 Bd de l’Hôpital, 75651, Paris cedex 13, France 5 Novartis Pharma France, 2–4 rue Lionel Terray, 92506, Rueil-Malmaison cedex, France 6 Novartis Institutes for BioMedical Research, 250 Massachusetts Avenue, Cambridge, MA 02139 USA Keywords: hypercholesterolemia, hypolipidemic response, pharmacogenetic Introduction: Marked lowering of low-density-lipoprotein cholesterol (LDL-C) levels (≤50%) with intensive statin therapy is associated with major reduction in cardiovascular risk, but is limited by a potential increase in adverse effects, thereby justifying optimization of LDL-C reduction with minimal risk. The organic anion transporting polypeptide-1B1 encoded by the SLCO1B1 gene is implicated as a major transporter in cellular uptake of statins, and notably fluvastatin. We postulated that genetic variation in SLCO1B1 might affect statin bioavailability, and might therefore influence drug response and potential adverse effects. Materials & methods: Elderly hypercholesterolemic subjects (n = 724), whose plasma lipid profile was determined before and 2 months after fluvastatin extended-release treatment (80 mg/day, n = 420), or placebo (n = 304), were genotyped for the most frequent nonsynonymous polymorphisms (SNP) in the SLCO1B1 gene (c.388A>G, c.463C>A and c.521T>C). Results: Due to linkage disequilibrium, only four alleles (* 1b, *5, * 14 and * 15) of SLCO1B1 were detected in addition to the wild-type allele (* 1a). The c.463A genotype, which was systematically associated with the c.388G SNP corresponding to the * 14 allele was significantly associated with percentage LDL-C reduction from baseline (p = 0.005) and with mean post-treatment LDL-C values (p = 0.0005). Subjects homozygous for the c.463C genotype (n = 294) exhibited significantly less LDL-C reduction and higher post-treatment LDL-C levels (-31.5%, 138 mg/dl) relative to heterozygous C/A patients (-36.2%, 126 mg/dl; n = 111), and to homozygous A/A subjects (-41%, 115 mg/dl; n = 15). Conclusions: These results reveal that OATP1B1 is implicated in the pharmacological action and efficacy of fluvastatin. Indeed, the common * 14 allele, which is distinguished by the presence of the c.463C>A polymorphism, was associated with enhanced lipid-lowering efficacy in this study. Statins are highly efficacious not only in reduc- ing circulating concentrations of atherogenic low-density-lipoprotein cholesterol (LDL-C), but also cardiovascular morbimortality. T he Cholesterol Treatment Trialist (CT T ) meta- analysis, which compiled data from 14 random- ized clinical trials involving more than 90,000 participants, revealed that a statin-mediated reduction of 1 mmol/l (40 mg/dl) in LDL-C sustained for 5 years typically produces a pro- portional reduction in major vascular events of approximately 23% [1]. Four recent trials (PROVE IT-TIMI 22, TNT, A to Z and ID EAL) have suggested that greater reductions in LDL-C, which may be attained with inten- sive statin therapy, are associated with larger reductions in vascular disease risk [2–5]. How- ever, the risk of adverse effects, such as myopa- thy, tends to increase with increasing statin dose [6,7]. Indeed, increase in circulating statin concentration is associated with the risk of myo- toxicity [8]. Therefore, the management of dyslipidemia with high-dose statins aims at maximizing reduction of LDL-C with minimal risk of adverse effects, which in turn requires more comprehensive understanding of the molecular basis underlying interindividual variability in the response to statin treatment. HMG-CoA reductase inhibitors target the rate-limiting step in the de novo synthesis of cho- lesterol in hepatocytes. In addition to its role as the target organ, the liver plays an essential role in drug clearance from the circulation and elimi- nation through metabolic processes catalyzed by several cytochrome P450 isoenzymes [9]. Hepatic uptake of statins has been demonstrated to be mediated in an active energy-dependent manner by organic anion-transporting polypeptides (OAT Ps). T hese OAT Ps are transmembrane pro- teins expressed in the basolateral membrane of hepatocytes [10–14]. Statin OAT P-mediated cellu- lar uptake not only represents the first step of hepatic drug elimination, but is also a drug delivery system to the liver as the target organ [15]. Such transport therefore potentially influences both the pharmacokinetics and For reprint orders, please contact: reprints@futuremedicine.com