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Hepatic Metabolism and Transporter Gene Variants Enhance Response to Rosuvastatin in Patients With Acute Myocardial Infarction

The GEOSTAT-1 Study

Kristian M. Bailey, MBChB, Simon P.R. Romaine, BSc, Beryl M. Jackson, RGN, Amanda J. Farrin, MSc, Maria Efthymiou, MSc, Julian H. Barth, MD, Joanne Copeland, BSc,Terry McCormack, MBBS, Andrew Whitehead, MSc, Marcus D. Flather, MBBS, Nilesh J. Samani, MD, FMedSci, Jane Nixon, PhD, Alistair S. Hall, MD, PhD, Anthony J. Balmforth, PhD and on behalf of the SPACE ROCKET Trial Group

Author Affiliations

From the Division of Cardiovascular and Diabetes Research (K.M.B., S.P.R.R., B.M.J., A.J.B.), and Division of Cardiovascular and Neuronal Remodelling (A.S.H.), Multidisciplinary Cardiovascular Research Centre, Leeds Institute of Genetics, Health and Therapeutics, University of Leeds, Leeds, United Kingdom; Clinical Trials Research Unit (A.J.F., M.E., J.C., J.N.), University of Leeds, Leeds, United Kingdom; Clinical Biochemistry (J.H.B.), Leeds General Infirmary, Leeds, United Kingdom; Whitby Group Practice (T.M.), Spring Vale Medical Centre, Whitby, North Yorkshire, United Kingdom; Pharmacy Department (A.W.), Leeds General Infirmary, Leeds, United Kingdom; Clinical Trials and Evaluation Unit (M.D.F.), Royal Brompton and Harefield NHS Trust and Imperial College, London, United Kingdom; and Department of Cardiovascular Sciences (N.J.S.), University of Leicester, Leicester, United Kingdom.

Correspondence to Alistair S. Hall, Clinical Cardiology, Multidisciplinary Cardiovascular Research Centre (MCRC), G Floor, Jubilee Building, Leeds General Infirmary, Leeds, LS1 3EX, United Kingdom. E-mail A.S.Hall@leeds.ac.uk

* Dr Bailey, Mr Romaine, Dr Hall, and Dr Balmforth contributed equally to this study.

Abstract

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— The Genetic Effects On STATins (GEOSTAT-1) Study was a genetic substudy of Secondary Prevention of Acute Coronary Events—Reduction of Cholesterol to Key European Targets (SPACE ROCKET) (a randomized, controlled trial comparing 40 mg of simvastatin and 10 mg of rosuvastatin) that recruited 601 patients after myocardial infarction. We genotyped the following functional single nucleotide polymorphisms in the genes coding for the cytochrome P450 (CYP) 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 breast cancer resistance protein (BCRP; 421C>A). We assessed 3-month LDL cholesterol levels and the proportion of patients reaching the current LDL cholesterol target of <70 mg/dL (<1.81 mmol/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 that patients with at least 1 variant CYP3A5 and/or BCRP allele (n=186) were more likely to achieve the LDL cholesterol target (odds ratio: 2.289; 95% CI: 1.157, 4.527; P=0.017; rosuvastatin 54.0% to target vs simvastatin 33.7%). There were no differences for patients with variants of CYP2C9, CYP2C19, or SLCO1B1 in comparison with 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; odds ratio: 1.207; 95% CI: 0.768, 1.899; P=0.415).

Conclusion— The LDL cholesterol target was achieved more frequently for the 1 in 3 patients with CYP3A5 and/or BCRP variant genotypes when prescribed rosuvastatin 10 mg, compared with simvastatin 40 mg.

Clinical Trial Registration— URL: http://isrctn.org. Unique identifier: ISRCTN 89508434.

SOURCE:

Circulation: Cardiovascular Genetics.2010; 3: 276-285

Published online before print March 5, 2010,

doi: 10.1161/ CIRCGENETICS.109.898502