多个癫痫相关基因多态性与拉莫三嗪治疗儿童癫痫血药浓度的相关性

楼江; 林能明; 陈玲; 刘占利; 王薇; 王飞; 李晴宇; 严伟

doi:10.16766/j.cnki.issn.1674-4152.001718

多个癫痫相关基因多态性与拉莫三嗪治疗儿童癫痫血药浓度的相关性

doi: 10.16766/j.cnki.issn.1674-4152.001718

楼江^{1, 2},
林能明^{1, 2},
陈玲¹,
刘占利³,
王薇⁴,
王飞¹,
李晴宇¹,
严伟^1, ,

1.
浙江大学医学院附属杭州市第一人民医院药学部，浙江杭州 310006
2.
浙江省临床肿瘤药理与毒理学研究重点实验室，浙江杭州 310006
3.
浙江大学医学院附属杭州市第一人民医院儿科，浙江杭州 310006
4.
浙江大学医学院附属杭州市第一人民医院护理部，浙江杭州 310006

基金项目:

浙江省医药卫生科技计划项目 2018RC061

浙江省药学会医院药学专项科研自助基金 2016ZYY14

浙江省临床肿瘤药理与毒理学研究重点实验室资助 2020E10021

浙江省医学重点学科资助项目浙卫办[2018]2号

详细信息

通讯作者:
严伟，E-mail: yanwei_115@163.com

中图分类号: R742.1 R969
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出版历程
- 收稿日期: 2019-08-08
- 网络出版日期: 2022-02-19

Correlation between multiple epilepsy related gene polymorphisms and serum concentrations of lamotrigine in the treatment of epilepsy in children

LOU Jiang^{1, 2},
LIN Neng-ming^{1, 2},
CHEN Ling¹,
LIU Zhan-li³,
WANG Wei⁴,
WANG Fei¹,
LI Qing-Yu¹,
YAN Wei^{1
, ,}

1.
Department of Clinical Pharmacy, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310006, China

摘要

摘要: 目的拉莫三嗪是儿童癫痫的一线治疗药物，其血药浓度与临床疗效个体差异较大，药效学和药动学通路多个相关基因突变可能是个体差异大的原因，本研究探讨代谢酶UGT1A4，转运体OCT1与ABCB1，受体SCN1A基因多态性与拉莫三嗪治疗儿童癫痫稳态血药浓度的相关性。方法于2018年1月—2019年6月纳入杭州市第一人民医院单用拉莫三嗪治疗的49例癫痫儿童，采集拉莫三嗪治疗达稳定剂量超过7 d以上患儿的稳态谷浓度血浆，使用高效液相色谱法测定拉莫三嗪血药浓度，直接测序法分析代谢酶UGT1A4(rs2011425)、转运体OCT1(rs628031)、ABCB1(rs1045642与rs1128503)和受体SCN1A(rs3812718)的基因分型。采用Kruskal-Wallis H检验或Mann-Whitney U检验探究不同基因分型与拉莫三嗪(LTG)血药浓度及标准化血药浓度相关性[即LTG血浆药物浓度除以每日每千克体重的服药剂量, CDR，(μg/mL)/(mg/kg)]，P < 0.05为具有显著相关性。结果转运体OCT1 rs628031与拉莫三嗪CDR具有显著相关性，其中AA+AG携带者CDR值显著高于GG携带者，分别是1.27(1.03, 2.20)和0.69(0.57, 1.02)，P=0.002；但其他基因型与CDR值无显著相关性。结论 CT1 rs628031基因突变可能是拉莫三嗪血药浓度和临床疗效个体差异大的重要因素。
- 拉莫三嗪 /
- 血药浓度 /
- 尿苷二磷酸葡糖苷酸转移酶1A4 /
- 有机阳离子转运体1 /
- ATP结合盒B亚家族成员1 /
- 电压门控钠离子通道a1亚单位
Abstract: Objective To evaluated that association between UGT1A4, OCT1, ABCB1 and SCN1A polymorphisms and blood concentration of lamotrigine in pediatric epilepsy patients. Methods A total of 49 pediatric epilepsy patients treated with lamotrigine alone in Hangzhou First People's Hospital were enrolled from January 2018 to June 2019. Steady-state plasma concentrations of lamotrigine were collected for a stable dose of consecutive 7 days and above. High performance liquid chromatography was used to measure blood concentrations of lamotrigine. Collect whole blood and analyzed the metabolic enzymes UGT1A4 (rs2011425), transporter OCT1 (rs628031), ABCB1 (rs1045642 and rs1128503) and receptor SCN1A (rs3812718) gene polymorphisms by direct sequencing. The correlation between different genotypes and the dose-normalized blood concentration of lamotrigine [the blood concentration of lamotrigine divided by the daily dose and the patient's body weight per kilogram, Concentration-to-dose-ratio by body weight, CDR, (μg/mL)/(mg/kg)] were investigated by using Kruskal-Wallis H test or Mann-Whitney U test. P < 0.05 was considered statistically significant. Results There was significant associations between OCT1 rs628031 polymorphism and lamotrigine CDR, compared with AA and AG genotypes, GG genotype of OCT1 rs628031 was associated with lower LTG CDR [AA + AG vs. GG: 1.27(1.03, 2.20) and 0.69(0.57, 1.02), P=0.002]. No associations were detected between other genotypes and lamotrigine CDR. Conclusion OCT1 rs628031 polymorphisms maybe an important factor for the inter-individual in blood concentration and clinical efficacy of lamotrigine.
- Lamotrigine /
- Blood concentration /
- UDP-glcumnosyltcansferase1A4 /
- Organic cation transporter 1 /
- ATP-binding cassette subfamily B member 1 /
- Voltage-gated sodium channel a1-subunit

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图 1 高效液相色谱图

注：A为空白血浆；B为空白血浆加LTG+MHD+OXC+内标的色谱图；C为患者服用拉莫三嗪50 mg每天2次的稳态谷浓度血浆样品+内标。

下载: 全尺寸图片幻灯片

表 1 各基因型分布情况[例(%)]

基因型	等位基因频率(%)		野生纯合子^a		突变杂合子^a		突变纯合子^a		χ²值	P值
基因型	野生型	突变型	实际值	理论值	实际值	理论值	实际值	理论值	χ²值	P值
UGT1A4 rs2011425	T(82.7)	G(17.3)	32.0(65.3)	33.5(68.4)	17.0(34.7)	14.0(28.6)	0.0(0.0)	1.5(3.0)	2.341	0.310
SLC22A1 rs628031	G(76.7)	A(23.4)	31.0(63.3)	28.8(58.8)	13.0(26.5)	17.6(35.9)	5.0(10.2)	2.6(5.3)	1.363	0.506
C3435T rs1045642	C(57.2)	T(42.8)	16.0(32.7)	16.0(32.7)	24.0(49.0)	24.0(49.0)	9.0(18.3)	9.0(18.3)	< 0.001	>0.999
C1236T rs1128503	C(31.6)	T(68.4)	8.0(16.3)	4.9(10.0)	15.0(30.6)	21.2(43.3)	26.0(53.1)	22.9(46.7)	1.876	0.391
SCN1A rs3812718	G(41.8)	A(58.2)	11.0(22.4)	8.6(17.6)	19.0(38.8)	23.8(48.6)	19.0(38.8)	16.6(33.8)	0.882	0.643
注：χ²值是每个基因型的实际值和理论值之间吻合程度，P值表示基因型实际值和理论值之间有无显著性差异。^a为基因型分布。

下载: 导出CSV

表 2 UGT1A4、ABCB1、OCT1和SCN1A基因多态性与LTG稳态血药浓度和CDR的相关性

SNP	基因型	例数	LTG浓度(μg/mL)	统计量	P值	CDR	统计量	P值
UGT1A4 rs2011425(T>G)	TT	32	3.80(3.10, 4.98)	251.500^a	0.667	0.96(0.64, 1.59)	243.500^a	0.549
	TG	17	4.44(1.73, 5.91)			0.92(0.55, 1.71)
OCT1 rs628031(A>G)	GG	31	3.40(2.04, 4.65)	5.100^b	0.078	0.69(0.57, 1.02)	10.190^b	0.006
	GA	13	4.07(3.43, 6.19)			1.19(1.00, 2.32)
	AA	5	7.15(3.75, 8.23)			1.93(1.11, 2.41)
	AA+AG	18	4.32(3.61, 7.58)			1.27(1.03, 2.20)^c
ABCB1 rs1045642(C>T)	CC	16	3.98(2.18, 4.88)	0.331^b	0.848	0.99(0.58, 1.74)	0.183^b	0.913
	CT	24	3.53(2.22, 4.88)			0.95(0.53, 1.65)
	TT	9	3.88(3.32, 4.86)			0.94(0.94, 1.38)
ABCB1 rs1128503(C>T)	CC	8	2.84(1.59, 4.54)	2.141^b	0.343	0.90(0.58, 1.22)	0.948^b	0.623
	CT	15	3.71(1.91, 8.40)			0.70(0.47, 1.93)
	TT	26	3.90(3.28, 4.99)			1.00(0.62, 1.78)
SCN1A rs3812718(G>A)	GG	11	3.99(1.77, 7.89)	0.747^b	0.688	1.06(0.63, 2.64)	1.310^b	0.519
	GA	19	3.40(2.22, 4.98)			0.81(0.58, 1.27)
	AA	19	4.07(3.06, 4.81)			0.98(0.56, 1.63)
注：^a为U值，^b为H值。与GG比较，^cP < 0.05。

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参考文献(22)

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