钙调神经磷酸酶基因多态性对环孢素A药效的影响
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篇名: 钙调神经磷酸酶基因多态性对环孢素A药效的影响
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摘要: 目的:研究钙调神经磷酸酶基因多态性对环孢素A(CsA)药效的影响。方法:收集服用CsA患者的血样,采用酶放大免疫法检测CsA谷浓度,以限制性片段长度多态性-聚合酶链反应(RFLP-PCR)方法检测PPP3CA和PPP3CB的基因型,以T细胞核因子(NFAT)下游基因白细胞介素(IL)2、γ干扰素(IFN-γ)和粒-巨噬细胞集落刺激因子(GM-CSF)的表达作为CsA间接药效指标,并采用实时定量PCR(RT-qPCR)法检测其表达,利用相关性分析和多因素回归等方法研究基因多态性与CsA药效的关系。结果:共收集CsA血液样本100份,CsA药效相关的NFAT下游基因GM-CSF的表达与CsA谷浓度无显著性相关(rGM-CSF=-0.04,P=0.238),IL-2和IFN-γ的表达与CsA谷浓度存在显著性负相关(rIL-2=-0.384 3,P<0.001; rIFN-γ=-0.335 4,P<0.001)。以IL-2和IFN-γ mRNA表达均数作为间接药效指标,发现PPP3CB rs3763679 位点基因多态性对CsA药效有显著性影响(P<0.05),而未发现PPP3CA rs3804358对药效有明显影响(P>0.05)。分层分析结果显示,肾移植和免疫病患者中PPP3CB rs3763679基因变异(TC+TT)的患者药效优于野生型(CC)(P<0.05)。将药效以浓度标化后,多因素回归分析显示CsA浓度标化后的药效与患者性别、 PPP3CB rs3763679、 乳酸脱氢酶和肌酐呈显著性负相关,与 PPP3CA rs3804358 、白细胞计数、尿素氮和三酰甘油等呈显著性正相关。结论:PPP3CB rs3763679基因多态性对CsA药效有影响,在肾移植和免疫性疾病患者中,PPP3CB rs3763679 TT+TC者药效优于CC者;同时,性别、PPP3CA rs3804358、白细胞计数、乳酸脱氢酶、肌酐、尿素氮和三酰甘油等多种因素皆可不同程度影响标化后CsA药效,在给予CsA时也需同时考虑多方面的因素。
ABSTRACT: OBJECTIVE: To study the influence of calcineurin gene polymorphism on the efficacy of cyclosporine A (CsA). METHODS: The blood samples of patients treated with CsA were collected. The trough blood concentration of CsA was detected by EMIT. The genotype of PPP3CA and PPP3CB was assayed by RFLP-PCR method. The expression of NFAT-regulated gene IL-2, IFN-γ and GM-CSF were measured by RT-qPCR, which were used to define the index of indirect efficacy of CsA. The relationship of gene polymorphism with CsA efficacy was study by relationship analysis and multiple factor regression method, etc. RESULTS: A total of 100 blood samples were collected. There was no significant correlation between the expression of CsA efficacy-related NFAT-regulated gene GM-CSF and trough concentration of CsA (rGM-CSF=-0.04,P=0.238); the expression of IL-2 and IFN-γ were negatively correlated with trough concentration of CsA significantly (rIL-2=-0.384 3,P<0.001; rIFN-γ=-0.335 4,P<0.001). Using the average value of mRNA expression of IL-2 and IFN-γ as indirect efficacy index, the polymorphism of PPP3CB rs3763679 site significantly influenced the efficacy of CsA (P<0.05), but PPP3CA rs3804358 had no any effect on it (P>0.05). Stratified analysis showed that among patients with immune disease underwent renal transplantation, efficacy of patients with PPP3CB rs3763679 genovariation (TC+TT) were better than those with wild-type gene (CC) (P<0.05). After the efficacy was normalized by CsA trough concentration, multivariate analysis showed that normalized efficacy of CsA was negatively correlated with gender, PPP3CB rs3763679, lactate dehydrogenase and creatinine significantly, but positively correlated with PPP3CA rs3804358, leucocyte count, usea nitrogen, glycerin trilaurate, etc. CONCLUSIONS: PPP3CB rs3763679 gene polymorphism influence the efficacy of CsA; among patients with immune disease underwent renal transplantation, efficacy of patients with PPP3CB rs3763679 TT+TC is better than that of CC type. At the same time, gender, PPP3CA rs3804358, leucocyte count, usea nitrogen, glycerin trilaurate and other factors all can influence the normalized efficacy of CsA to different extent. Multiple factors should be considered when using CsA.
期刊: 2016年第27卷第29期
作者: 姚婧,海英民,陈丁丁,葛卫红,朱怀军
AUTHORS: YAO Jing,HAI Yingmin,CHEN Dingding,GE Weihong,ZHU Huaijun
关键字: 钙调神经磷酸酶;环孢素A;个体化给药;基因多态性
KEYWORDS: Calcineurin; CyclosporinA; Individual administration; Gene polymorphism
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