Effects of SLCO1B1 and GATM gene variants on rosuvastatin-induced myopathy are unrelated to high plasma exposure of rosuvastatin and its metabolites
Effects of SLCO1B1 and GATM gene variants on rosuvastatin-induced myopathy are unrelated to high plasma exposure of rosuvastatin and its metabolites
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SLCO1B1 和 GATM 基因变异对瑞舒伐他汀诱导的肌病的影响与瑞舒伐他汀及其代谢物的高血浆暴露无关
DOI：
10.1038/s41401-018-0013-y
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发表时间：
2019-04-01
影响因子：
8.2
通讯作者：
Zhong, Shi-long
中科院分区：
文献类型：
--
作者：
Bai, Xue;Zhang, Bin;Zhong, Shi-long
肌肉毒性是导致他汀类药物治疗依从性差和有效性降低的重要因素。遗传变异和高药物血浆暴露被认为是他汀类药物诱导的肌病（SIM）的关键原因。本研究旨在探讨瑞舒伐他汀（瑞舒伐他汀）药代动力学和肌病相关单核苷酸多态性（SNP）对瑞舒伐他汀及其代谢产物瑞舒伐他汀内酯（RSTL）和N-去甲基瑞舒伐他汀（DM-RSTL）血浆暴露的顺序影响，并进一步对RST诱导的肌病的影响。入选758例中国冠心病患者，随访SIM事件2年。通过经验证的超高效液相色谱-质谱法测定血浆中的阿托伐他汀及其代谢产物的浓度。通过使用Sequenom MassArray iPlex平台对6个基因中的9个SNP进行基因分型。结果显示，ABCG 2 rs 2231142变异与血浆中的RSTL、RSTL和DM-HDL浓度高度相关（P-adj < 0.01，FDR < 0.05）。CYP 2C 9 rs 1057910显著影响DM-DR浓度（P-adj < 0.01，FDR < 0.05）。SLCO 1B 1 rs 4149056变异等位基因与SIM高风险显著相关（OR：1.741，95%CI：1.180-2.568，P = 0.0052，FDR = 0.0468）。甘氨酸脒基转移酶（GATM）rs 9806699与SIM事件轻微相关（OR：0.617，95%CI：0.406-0.939，P = 0.0240，FDR = 0.0960）。SIM组（n = 51）和对照组（n = 707）血浆中的β-内酰胺酶及其代谢产物浓度差异均无统计学意义（均P > 0.05）。总之，SLCO 1B 1和GATM基因变异是预测RST诱导的肌病的潜在生物标志物，它们对SIM的影响与高血浆暴露的RESINS及其代谢产物无关。
Myotoxicity is a significant factor contributing to the poor adherence and reduced effectiveness in the treatment of statins. Genetic variations and high drug plasma exposure are considered as critique causes for statin-induced myopathy (SIM). This study aims to explore the sequential influences of rosuvastatin (RST) pharmacokinetic and myopathy-related single-nucleotide polymorphisms (SNPs) on the plasma exposure to RST and its metabolites: rosuvastatin lactone (RSTL) and N-desmethyl rosuvastatin (DM-RST), and further on RST-induced myopathy. A total of 758 Chinese patients with coronary artery disease were enrolled and followed up SIM incidents for 2 years. The plasma concentrations of RST and its metabolites were determined through a validated ultra-performance liquid chromatography mass spectrometry method. Nine SNPs in six genes were genotyped by using the Sequenom MassArray iPlex platform. Results revealed that ABCG2 rs2231142 variations were highly associated with the plasma concentrations of RST, RSTL, and DM-RST (P-adj < 0.01, FDR < 0.05). CYP2C9 rs1057910 significantly affected the DM-RST concentration (P-adj < 0.01, FDR < 0.05). SLCO1B1 rs4149056 variant allele was significantly associated with high SIM risk (OR: 1.741, 95% CI: 1.180-2.568, P = 0.0052, FDR = 0.0468). Glycine amidinotransferase (GATM) rs9806699 was marginally associated with SIM incidents (OR: 0.617, 95% CI: 0.406-0.939, P = 0.0240, FDR = 0.0960). The plasma concentrations of RST and its metabolites were not significantly different between the SIM (n = 51) and control groups (n = 707) (all P > 0.05). In conclusion, SLCO1B1 and GATM genetic variants are potential biomarkers for predicting RST-induced myopathy, and their effects on SIM are unrelated to the high plasma exposure of RST and its metabolites.