Changes in PCSK9 and LDL cholesterol concentrations by everolimus treatment and their effects on polymorphisms in PCSK9 and mTORC1
Changes in PCSK9 and LDL cholesterol concentrations by everolimus treatment and their effects on polymorphisms in PCSK9 and mTORC1
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DOI：
10.1007/s43440-020-00090-6
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发表时间：
2020-03-25
影响因子：
4.4
通讯作者：
Miura, Masatomo
中科院分区：
文献类型：
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作者：
Sato, Shiori;Akamine, Yumiko;Miura, Masatomo
本研究的目的是评价哺乳动物雷帕霉素（mTOR）抑制剂依维莫莫对53例肾移植受者的PCSK9和mTORC1基因遗传多态性的影响，以及它们对PCSK9和mTORC1基因多态性的影响。方法在给药前和给药后第15天检测各组大鼠依维莫司血药浓度和血浆PCSK9、LDL胆固醇水平。此外，还分析了mTORC1 （rs2536T>C和rs2295080T>G）和PCSK9 （rs505151G>A、rss562556g >A和rs11593680C>T）多态性。结果依维莫司治疗后第15天PCSK9平均血浆浓度显著高于治疗前（分别为295 ng/mL和214 ng/mL， p = 0.004）。依维莫司治疗第15天血药浓度-时间曲线下面积（AUC）（0 ~ 12）与PCSK9浓度变化率呈显著相关（r = 0.316, p = 0.021）。然而，PCSK9变化率与LDL胆固醇浓度之间没有显著相关性。携带mTORC1 rs2295080G等位基因的患者接受依维莫司治疗后PCSK9浓度的变化率显著高于T/T基因型患者（p = 0.006）；然而，PCSK9 rs505151G>A和rs11583680C>T基因型之间没有显著差异。在多因素分析中，mTORC1 rs2295080G （p = 0.010）、依维莫司AUC较高（0-12）（p = 0.006）和女性（p = 0.029）的患者在依维莫司治疗后PCSK9变化率较高。结论依维莫司可显著提高血浆PCSK9浓度，可能引起依维莫司诱导的高脂血症。
Background The purpose of this study was to evaluate the effects of concentrations of proprotein convertase subtilisin/kexin type 9 (PCSK9) and low-density lipoprotein (LDL) cholesterol by the mammalian target of rapamycin (mTOR) inhibitor everolimus and their effects on genetic polymorphisms in the PCSK9 and mTORC1 genes in 53 renal transplant recipients. Methods Prior to and on day 15 after everolimus administration, the concentrations of everolimus in blood and PCSK9 and LDL cholesterol in plasma were evaluated. Additionally, mTORC1 (rs2536T>C and rs2295080T>G) and PCSK9 (rs505151G>A, rs562556G>A, and rs11593680C>T) polymorphisms were analyzed. Results Mean PCSK9 plasma concentrations on day 15 after everolimus treatment were significantly higher than those before treatment (295 versus 214 ng/mL, respectively; p = 0.004). Significant correlations between the area under the blood concentration-time curves (AUC)(0-12) on day 15 of everolimus treatment and the change rate in PCSK9 concentrations were found (r = 0.316, p = 0.021). However, there were no significant correlations between the change rate in PCSK9 and LDL cholesterol concentrations. The change rate in PCSK9 concentrations by everolimus treatment was significantly greater in patients with the mTORC1 rs2295080G allele than the T/T genotype (p = 0.006); however, there were no significant differences between PCSK9 rs505151G>A and rs11583680C>T genotypes. In multivariate analyses, patients with mTORC1 rs2295080G (p = 0.010), higher everolimus AUC(0-12) (p = 0.006), and female sex (p = 0.029) showed higher change rates of PCSK9 following everolimus therapy. Conclusions Administration of everolimus significantly elevated plasma PCSK9 concentrations, potentially causing everolimus-induced hyperlipidemia.