CYP2C19基因多态性对肺部侵袭性真菌感染患儿伏立康唑血药谷浓度的影响及其潜在机制

Effect of CYP2C19 gene polymorphism on the blood minimum concentration of voriconazole in children with invasive pulmonary fungal infection and its potential mechanisms

目的探究CYP2C19基因多态性对肺部侵袭性真菌感染患儿伏立康唑血药谷浓度的影响及其潜在机制。方法收集2013年9月-2021年9月广州医科大学附属第一医院儿科收治的因治疗和预防侵袭性真菌感染使用过伏立康唑的58例患儿的临床资料[包括基本信息,谷丙转氨酶(ALT)、C反应蛋白(CRP)和白介素-6(IL-6)水平]进行回顾性分析。抽取患儿外周血,使用基因芯片法检测CYP2C19基因型,高效液相色谱法检测血药浓度。根据药物浓度将患儿分为低浓度组和正常浓度组。比较不同血药浓度患儿基因型的差异;采用二元logistics回归分析影响患儿伏立康唑血药浓度的因素。结果58例患儿中4例拒绝行CYP2C19基因型检测,共检测54例,其中男35例,女19例。在6种CYP2C19基因型中,^(*)1/^(*)1(636 GG,681 GG)基因型患儿最多(30例),其余依次为^(*)1/^(*)2(636 GG,681 GA)基因型(20例)、^(*)1/^(*)3(636 GA,681 GG)基因型(2例)和^(*)2/^(*)3(636 GA,681 GA)基因型(2例),无^(*)2/^(*)2(636 GG,681 AA)基因型和^(*)3/^(*)3(636 AA,681 GG)基因型患儿。基因表型中快代谢型最多,30例;其次为中代谢型和慢代谢型,分别为22例和2例。等位基因CYP2C19^(*)1的频率最高(82例),其次为CYP2C19^(*)2和CYP2C19^(*)3(分别o 22例和4例)。基因型和等位基因与伏立康唑药谷浓度明显相关,与中、慢代谢型表型比较,快代谢型表型可明显降低伏立康唑的血药谷浓度。与CYP2C19^(*)2和CYP2C19^(*)3等位基因比较,CYP2C19^(*)1等位基因可明显降低伏立康唑药物浓度。二元logistics回归分析结果显示,BMI、CRP、IL-6和基因型可明显影响伏立康唑血药谷浓度。结论CYP2C19基因型以^(*)1/^(*)1(636 GG,681 GG)基因型为主,表型以快代谢型最多,等位基因以CYP2C19^(*)1最常见。炎性因子、BMI和基因型可明显影响伏立康唑的药物代谢。

Objective To explore the effect and potential mechanism of CYP2C19 gene polymorphism on the blood minimum concentration of voriconazole in children with invasive pulmonary fungal infection.Methods The clinical data of 58 children,who used voriconazole for treatment and prevention of invasive fungal infection in the Department of Pediatrics of the First Affiliated Hospital of Guangzhou Medical University from September 2013 to September 2021,were collected and analyzed retrospectively,including demographic information,glutamic-pyruvic transaminase(ALT),C-reactive protein(CRP)and interleukin-6(IL-6).The CYP2C19 genotype of children was detected by gene chip method,and the blood drug concentration was detected by high performance liquid chromatography.According to the drug concentration,the children were divided into low concentration group and normal concentration group.The difference of blood drug concentration in patients with different genotypes was compared.Binary logistic regression analysis was performed to analyze the factors affecting the blood concentration of voriconazole in children.Results Four of the 58 children refused to make gene test,the rest 54 patients including 35 males and 19 females;Among the six CYP2C19 genotypes,most children were with^(*)1/^(*)1(636 GG,681 GG)genotype(30 cases);The others were^(*)1/^(*)2(636 GG,681 GA)genotype(20 cases),^(*)1/^(*)3(636 GA,681 GG)genotype(2 cases),and^(*)2/^(*)3(636 GA,681 GA)genotype(2 cases),children without^(*)2/^(*)2(636 GG,681 AA)genotype and^(*)3/^(*)3(636 AA,681 GG)genotype.Among the gene phenotypes,extensive metabolizer type was the highest(30 cases),followed by intermediate metabolizer type and poor metabolizer type(22 cases and 2 cases,respectively).The frequency of allele CYP2C19^(*)1 was the highest(82 cases),followed by the allele CYP2C19^(*)2 and CYP2C19^(*)3(22 cases and 4 cases,respectively).Genotype and allele were significantly correlated with voriconazole minimum concentration.Compared with intermediate metabolizer and poor metabolizer,extensive metabolizer significantly reduced voriconazole minimum concentration.Compared with CYP2C19^(*)2 and CYP2C19^(*)3 alleles,CYP2C19^(*)1 allele significantly reduced the concentration of voriconazole.Binary logistic regression analysis demonstrated that BMI,CRP,IL-6 and genotype can significantly affect the blood minimum concentration of voriconazole.Conclusions The genotype of CYP2C19 is mainly^(*)1/^(*)1(636 GG,681 GG),the extensive metabolizer genotype is the most,and the allele of CYP2C19^(*)1 is the most common.Inflammatory factors,BMI and genotype significantly affected voriconazole metabolism.