Bailey Kristian M, Romaine Simon P R, Jackson Beryl M, Farrin Amanda J, Efthymiou Maria, Barth Julian H, Copeland Joanne, McCormack Terry, Whitehead Andrew, Flather Marcus D, Samani Nilesh J, Nixon Jane, Hall Alistair S, Balmforth Anthony J
Division of Cardiovascular and Diabetes Research, Multidisciplinary Cardiovascular Research Centre, Leeds Institute of Genetics, Health and Therapeutics, University of Leeds, Leeds, United Kingdom.
Circ Cardiovasc Genet. 2010 Jun;3(3):276-85. doi: 10.1161/CIRCGENETICS.109.898502. Epub 2010 Mar 5.
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.
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, CYP2C92 (430C>T), CYP2C93 (1075A>C), CYP2C192 (681G>A), CYP3A51 (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).
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.
药物遗传学旨在使药物治疗的益处最大化并将风险最小化。我们的目标是研究肝脏代谢和转运体基因的常见变异对他汀类药物治疗降脂反应的影响。
他汀类药物的遗传效应（GEOSTAT-1）研究是急性冠状动脉事件二级预防——将胆固醇降至欧洲关键目标（SPACE ROCKET）（一项比较40mg辛伐他汀和10mg瑞舒伐他汀的随机对照试验）的遗传子研究，该研究招募了601例心肌梗死后患者。我们对编码细胞色素P450（CYP）代谢酶的基因中的以下功能性单核苷酸多态性进行了基因分型，即CYP2C92（430C>T）、CYP2C93（1075A>C）、CYP2C192（681G>A）、CYP3A51（6986A>G），以及肝脏摄取和外流转运体SLCO1B1（521T>C）和乳腺癌耐药蛋白（BCRP；421C>A）。我们评估了3个月时的低密度脂蛋白胆固醇水平以及达到当前低密度脂蛋白胆固醇目标值<70mg/dL（<1.81mmol/L）的患者比例。CYP3A5（P=0.006）或BCRP（P=0.010）变异基因型的患者对瑞舒伐他汀的反应增强。此外，多因素逻辑回归分析显示，至少有1个CYP3A5和/或BCRP变异等位基因的患者（n=186）更有可能达到低密度脂蛋白胆固醇目标（优势比：2.289；95%置信区间：1.157，4.527；P=0.017；瑞舒伐他汀达到目标的比例为54.0%，而辛伐他汀为33.7%）。与各自的野生型相比，CYP2C9、CYP2C19或SLCO1B1变异的患者没有差异，对于CYP3A5和BCRP最常见基因型的患者（n=415；优势比：1.207；95%置信区间：0.768，1.899；P=0.415），对他汀类药物反应也没有差异。
与40mg辛伐他汀相比，当给1/3具有CYP3A5和/或BCRP变异基因型的患者处方10mg瑞舒伐他汀时，更频繁地达到了低密度脂蛋白胆固醇目标。临床试验注册——网址：http://isrctn.org。唯一标识符：ISRCTN 89508434。
