Table_1_CYP2C19 metabolizer phenotypes may affect the efficacy of statins on lowering small dense low-density lipoprotein cholesterol of patients with coronary artery disease.docx

BackgroundDyslipidemia is a major cause of arteriosclerotic cardiovascular disease (ASCVD), and low-density lipoprotein cholesterol (LDL-C) is the profile to be reduced to prevent disease progression. Small dense low-density lipoprotein cholesterol (sdLDL-C) has been proven to be a more effective biomarker than LDL-C for ASCVD primary and secondary prevention. CYP2C19 is an important drug metabolism gene. This study aimed to investigate the relationship between sdLDL-C and coronary artery disease (CAD) risk factors and explore the influence of CYP2C19 metabolizer phenotypes on the sdLDL-C lowering efficacy of statins.
MethodsThis study recruited 182 patients with CAD and 200 non-CAD controls. Baseline laboratory indices of fasting blood were detected, including blood lipids, glucose, and creatinine. In addition, LDL-C subfractions were separated and quantified. Gene polymorphisms of SLCO1B1 and CYP2C19 were detected in patients with CAD. The LDL-C subfractions levels of patients with CAD were followed up after statin drug treatment.
ResultsTotal cholesterol, LDL-C, LDLC-2, LDLC-3, LDLC-4, LDLC-5, LDLC-6, LDLC-7, and sdLDL-C levels of patients with CAD were significantly higher than those in non-CAD controls. Meanwhile, sdLDL-C (AUC = 0.838) and LDLC-4 (AUC = 0.835) performed outstandingly in distinguishing patients with CAD from controls. Based on CYP2C19 metabolizer phenotypes, 113 patients with CAD were divided into the extensive metabolizer (EM, n = 49), intermediate metabolizer (IM, n = 52), and poor metabolizer (PM, n = 12) groups. The patients with IM and PM metabolizer phenotypes had better sdLDL-C lowering efficacy after taking statin drugs than patients with EM phenotype (P = 0.0268, FDR = 0.0536). The SLCO1B1 genotype had no significant impact on the efficacy of statins (P = 0.1611, FDR = 0.1611).
ConclusionsdLDL-C and LDLC-4 outperformed other blood lipids such as LDL-C for CAD risk screening. CYP2C19 metabolizer phenotypes had the potential to predict the efficacy of statins in lowering sdLDL-C.

背景 血脂异常是动脉粥样硬化性心血管疾病（arteriosclerotic cardiovascular disease, ASCVD）的主要致病因素，低密度脂蛋白胆固醇（low-density lipoprotein cholesterol, LDL-C）是预防疾病进展所需降低的靶标。研究证实，小而密低密度脂蛋白胆固醇（small dense low-density lipoprotein cholesterol, sdLDL-C）相较于LDL-C，是动脉粥样硬化性心血管疾病一、二级预防中更为有效的生物标志物。细胞色素P450 2C19（CYP2C19）是重要的药物代谢基因。本研究旨在探讨sdLDL-C与冠状动脉疾病（coronary artery disease, CAD）危险因素间的关联，并分析CYP2C19代谢型对他汀类药物降低sdLDL-C疗效的影响。
方法 本研究共纳入182例冠状动脉疾病患者与200例非冠状动脉疾病对照者。检测受试者空腹血液的基线实验室指标，包括血脂、血糖与肌酐。此外，分离并定量低密度脂蛋白胆固醇亚组分。对冠状动脉疾病患者，检测其SLCO1B1与CYP2C19基因多态性。对接受他汀类药物治疗的冠状动脉疾病患者，随访其低密度脂蛋白胆固醇亚组分水平。
结果 冠状动脉疾病患者的总胆固醇、LDL-C、LDLC-2、LDLC-3、LDLC-4、LDLC-5、LDLC-6、LDLC-7及sdLDL-C水平均显著高于非冠状动脉疾病对照者。同时，sdLDL-C（曲线下面积AUC=0.838）与LDLC-4（AUC=0.835）在区分冠状动脉疾病患者与对照者时表现优异。基于CYP2C19代谢型，113例冠状动脉疾病患者被分为快代谢型（extensive metabolizer, EM, n=49）、中间代谢型（intermediate metabolizer, IM, n=52）与慢代谢型（poor metabolizer, PM, n=12）三组。与EM表型患者相比，IM与PM表型患者服用他汀类药物后，sdLDL-C降低效果更显著（P=0.0268，错误发现率FDR=0.0536）。SLCO1B1基因型对他汀类药物疗效无显著影响（P=0.1611，FDR=0.1611）。
结论 sdLDL-C与LDLC-4在冠状动脉疾病风险筛查中，表现优于LDL-C等其他血脂指标。CYP2C19代谢型有望预测他汀类药物降低sdLDL-C的疗效。