基于多组学数据研究奥卡西平抗痫机制

摘要/Abstract

摘要： 目的

基于多组学数据探究奥卡西平靶基因与癫痫基因的相关性，探讨奥卡西平抗痫机制。

方法

借助DrugBank数据库检索奥卡西平靶基因，利用Magama软件及整合单细胞测序数据验证奥卡西平靶基因在全基因组关联分析（genome-wide association study，GWAS）层面与癫痫致病基因的相关性，应用Fisher检验验证奥卡西平靶基因与稀有变异癫痫危险基因存在显著遗传重叠，运用R软件进行奥卡西平靶基因富集，基于DAVID数据库对靶点进行基因本体功能富集分析和京都基因与基因组百科全书信号通路富集分析。

结果

共获得奥卡西平药物靶点25种，主要为钠离子通道、细胞色素P450家族成员、醛酮还原酶家族成员、血清白蛋白、羰基还原酶家族成员。通过癫痫GWAS数据基因集分析，奥卡西平靶基因与癫痫致病基因存在显著关联，且与单基因突变所致癫痫风险基因存在显著重叠，主要为电压门控钠离子通道。通过测序得出奥卡西平富集神经细胞类型主要为下丘脑GABA能神经元和中型多棘神经元。通过靶向富集途径分析，显示奥卡西平药物靶点显著富集在中枢神经系统钠离子通道中。

结论

基于生物信息学整合分析，奥卡西平可能通过作用于下丘脑GABA能神经元、中型多棘神经元中的钠离子通道基因发挥抗痫作用。

关键词:癫痫,奥卡西平,单细胞测序,全基因组关联分析,生物信息学

Abstract: Objective

To explore the relationship between oxcarbazepine target gene and epileptic gene based on multi-group data， and to explore the antiepileptic mechanism of oxcarbazepine.

Methods

The target gene of oxcarbazepine was searched by DrugBank database. Magama software and integrated single cell sequencing data were used to verify that there was significant association between oxcarbazepine target gene and epileptic pathogenic gene at GWAS level. Fisher test was used to verify that there was significant genetic overlap between oxcarbazepine target gene and rare variant epileptic risk gene. R software was used to enrich oxcarbazepine target gene. Gene ontology function enrichment analysis and Kyoto gene and genome encyclopedia signal pathway enrichment analysis were carried out based on DAVID database.

Results

A total of 25 kinds of oxcarbazepine drug targets were obtained， including sodium channels， cytochrome P450 family members， aldosterone reductase family members， serum albumin and carbonyl reductase family members. Through the gene set analysis of epileptic GWAS data， there is a significant association between oxcarbazepine target gene and epileptic pathogenic gene， and there is a significant "overlap" between oxcarbazepine target gene and epileptic risk gene caused by single gene mutation， which is mainly voltage-gated sodium channel. The main types of neurons enriched by oxcarbazepine were hypothalamic GABA neurons and medium spiny neuron. The analysis of targeted enrichment pathway showed that the drug targets of oxcarbazepine were significantly enriched in the sodium channels of the central nervous system.

Conclusion

Based on bioinformatics integration analysis， oxcarbazepine may play an antiepileptic effect by acting on sodium channel genes in hypothalamic GABA neurons and medium spiny neuron.

Key words:epilepsy,oxcarbazepine,single cell sequencing,genome-wide association analysis,bioinformatics

徐雯, 吕玉芹, 高蕾, 张敬军. 基于多组学数据研究奥卡西平抗痫机制[J]. betway必威登陆网址（betway.com ）学报, 2022, 43(5): 327-334.

Wen XU, Yuqin LV, Lei GAO, Jingjun ZHANG. Study on the antiepileptic mechanism of oxcarbazepine based on multi-group data[J]. Journal of Shandong First Medical Unversity & Shandong Academy of Medical Sciences, 2022, 43(5): 327-334.

图/表8

靶基因	靶基因全称	靶基因类型
SCN1A	Sodium channel protein type 1 subunit alpha	Target
SCN10A	Sodium channel protein type 10 subunit alpha	Target
SCN11A	Sodium channel protein type 11 subunit alpha	Target
SCN2A	Sodium channel protein type 2 subunit alpha	Target
SCN3A	Sodium channel protein type 3 subunit alpha	Target
SCN4A	Sodium channel protein type 4 subunit alpha	Target
SCN5A	Sodium channel protein type 5 subunit alpha	Target
SCN7A	Sodium channel protein type 7 subunit alpha	Target
SCN8A	Sodium channel protein type 8 subunit alpha	Target
SCN9A	Sodium channel protein type 9 subunit alpha	Target
SCN1B	Sodium channel subunit beta-1	Target
SCN2B	Sodium channel subunit beta-2	Target
SCN3B	Sodium channel subunit beta-3	Target
SCN4B	Sodium channel subunit beta-4	Target
AKR1C1	Aldo-keto reductase family 1 member C1	Enzyme
AKR1C2	Aldo-keto reductase family 1 member C2	Enzyme
AKR1C3	Aldo-keto reductase family 1 member C3	Enzyme
AKR1C4	Aldo-keto reductase family 1 member C4	Enzyme
CBR1	Carbonyl reductase ［NADPH］ 1	Enzyme
CBR3	Carbonyl reductase ［NADPH］ 3	Enzyme
CYP2C19	Cytochrome P450 2C19	Enzyme
CYP3A4	Cytochrome P450 3A4	Enzyme
CYP3A5	Cytochrome P450 3A5	Enzyme
ALB	Serum albumin	Carrier
ABCB1	Multidrug resistance protein 1	Transporter

靶基因	靶基因全称	靶基因类型
SCN1A	Sodium channel protein type 1 subunit alpha	Target
SCN10A	Sodium channel protein type 10 subunit alpha	Target
SCN11A	Sodium channel protein type 11 subunit alpha	Target
SCN2A	Sodium channel protein type 2 subunit alpha	Target
SCN3A	Sodium channel protein type 3 subunit alpha	Target
SCN4A	Sodium channel protein type 4 subunit alpha	Target
SCN5A	Sodium channel protein type 5 subunit alpha	Target
SCN7A	Sodium channel protein type 7 subunit alpha	Target
SCN8A	Sodium channel protein type 8 subunit alpha	Target
SCN9A	Sodium channel protein type 9 subunit alpha	Target
SCN1B	Sodium channel subunit beta-1	Target
SCN2B	Sodium channel subunit beta-2	Target
SCN3B	Sodium channel subunit beta-3	Target
SCN4B	Sodium channel subunit beta-4	Target
AKR1C1	Aldo-keto reductase family 1 member C1	Enzyme
AKR1C2	Aldo-keto reductase family 1 member C2	Enzyme
AKR1C3	Aldo-keto reductase family 1 member C3	Enzyme
AKR1C4	Aldo-keto reductase family 1 member C4	Enzyme
CBR1	Carbonyl reductase ［NADPH］ 1	Enzyme
CBR3	Carbonyl reductase ［NADPH］ 3	Enzyme
CYP2C19	Cytochrome P450 2C19	Enzyme
CYP3A4	Cytochrome P450 3A4	Enzyme
CYP3A5	Cytochrome P450 3A5	Enzyme
ALB	Serum albumin	Carrier
ABCB1	Multidrug resistance protein 1	Transporter

靶基因	靶基因ID	物种	靶基因全称
ABCB1	5243	Homo sapiens	ATP binding cassette subfamily B member 1（ABCB1）
CYP2C19	1557	Homo sapiens	cytochrome P450 family 2 subfamily C member 19（CYP2C19）
CYP3A4	1576	Homo sapiens	cytochrome P450 family 3 subfamily A member 4（CYP3A4）
CYP3A5	1577	Homo sapiens	cytochrome P450 family 3 subfamily A member 5（CYP3A5）
SCN11A	11280	Homo sapiens	sodium voltage-gated channel alpha subunit 11（SCN11A）
SCN9A	6335	Homo sapiens	sodium voltage-gated channel alpha subunit 9（SCN9A）
SCN7A	6332	Homo sapiens	sodium voltage-gated channel alpha subunit 7（SCN7A）
SCN5A	6331	Homo sapiens	sodium voltage-gated channel alpha subunit 5（SCN5A）
SCN3B	55800	Homo sapiens	sodium voltage-gated channel beta subunit 3（SCN3B）
SCN3A	6328	Homo sapiens	sodium voltage-gated channel alpha subunit 3（SCN3A）
SCN1B	6324	Homo sapiens	sodium voltage-gated channel beta subunit 1（SCN1B）
CBR3	874	Homo sapiens	carbonyl reductase 3（CBR3）
SCN1A	6323	Homo sapiens	sodium voltage-gated channel alpha subunit 1（SCN1A）
CBR1	873	Homo sapiens	carbonyl reductase 1（CBR1）
AKR1C1	1645	Homo sapiens	aldo-keto reductase family 1 member C1（AKR1C1）
AKR1C3	8644	Homo sapiens	aldo-keto reductase family 1 member C3（AKR1C3）
AKR1C2	1646	Homo sapiens	aldo-keto reductase family 1 member C2（AKR1C2）
AKR1C4	1109	Homo sapiens	aldo-keto reductase family 1 member C4（AKR1C4）
SCN10A	6336	Homo sapiens	sodium voltage-gated channel alpha subunit 10（SCN10A）
SCN8A	6334	Homo sapiens	sodium voltage-gated channel alpha subunit 8（SCN8A）
ALB	213	Homo sapiens	albumin（ALB）
SCN4A	6329	Homo sapiens	sodium voltage-gated channel alpha subunit 4（SCN4A）
SCN2A	6326	Homo sapiens	sodium voltage-gated channel alpha subunit 2（SCN2A）
SCN4B	6330	Homo sapiens	sodium voltage-gated channel beta subunit 4（SCN4B）
SCN2B	6327	Homo sapiens	sodium voltage-gated channel beta subunit 2（SCN2B）

靶基因	靶基因ID	物种	靶基因全称
ABCB1	5243	Homo sapiens	ATP binding cassette subfamily B member 1（ABCB1）
CYP2C19	1557	Homo sapiens	cytochrome P450 family 2 subfamily C member 19（CYP2C19）
CYP3A4	1576	Homo sapiens	cytochrome P450 family 3 subfamily A member 4（CYP3A4）
CYP3A5	1577	Homo sapiens	cytochrome P450 family 3 subfamily A member 5（CYP3A5）
SCN11A	11280	Homo sapiens	sodium voltage-gated channel alpha subunit 11（SCN11A）
SCN9A	6335	Homo sapiens	sodium voltage-gated channel alpha subunit 9（SCN9A）
SCN7A	6332	Homo sapiens	sodium voltage-gated channel alpha subunit 7（SCN7A）
SCN5A	6331	Homo sapiens	sodium voltage-gated channel alpha subunit 5（SCN5A）
SCN3B	55800	Homo sapiens	sodium voltage-gated channel beta subunit 3（SCN3B）
SCN3A	6328	Homo sapiens	sodium voltage-gated channel alpha subunit 3（SCN3A）
SCN1B	6324	Homo sapiens	sodium voltage-gated channel beta subunit 1（SCN1B）
CBR3	874	Homo sapiens	carbonyl reductase 3（CBR3）
SCN1A	6323	Homo sapiens	sodium voltage-gated channel alpha subunit 1（SCN1A）
CBR1	873	Homo sapiens	carbonyl reductase 1（CBR1）
AKR1C1	1645	Homo sapiens	aldo-keto reductase family 1 member C1（AKR1C1）
AKR1C3	8644	Homo sapiens	aldo-keto reductase family 1 member C3（AKR1C3）
AKR1C2	1646	Homo sapiens	aldo-keto reductase family 1 member C2（AKR1C2）
AKR1C4	1109	Homo sapiens	aldo-keto reductase family 1 member C4（AKR1C4）
SCN10A	6336	Homo sapiens	sodium voltage-gated channel alpha subunit 10（SCN10A）
SCN8A	6334	Homo sapiens	sodium voltage-gated channel alpha subunit 8（SCN8A）
ALB	213	Homo sapiens	albumin（ALB）
SCN4A	6329	Homo sapiens	sodium voltage-gated channel alpha subunit 4（SCN4A）
SCN2A	6326	Homo sapiens	sodium voltage-gated channel alpha subunit 2（SCN2A）
SCN4B	6330	Homo sapiens	sodium voltage-gated channel beta subunit 4（SCN4B）
SCN2B	6327	Homo sapiens	sodium voltage-gated channel beta subunit 2（SCN2B）

靶基因	靶基因ID	染色体位置	起始位置	终止位置	SNP数量	样本量	P值相关统计量	P
SCN1A	6 323	2	166835670	167040642	507	38 017	6.025	< 0.001
SCN9A	6 335	2	167041695	167267497	519	37 621	3.253	< 0.001
SCN7A	6 332	2	167250083	167378481	268	37 555	1.793	0.015
SCN3B	55 800	11	123489895	123560315	185	37 870	1.742	0.017
SCN11A	11 280	3	38877260	39030136	283	38 190	1.441	0.036
SCN10A	6 336	3	38728837	38870501	328	37 505	1.231	0.049
SCN1B	6 324	19	35486555	35541353	10	35 245	1.053	0.085
CYP2C19	1 557	10	96487463	96622671	285	38 149	1.020	0.090
SCN5A	6 331	3	38579553	38726164	242	37 201	0.788	0.103
CYP3A4	1 576	7	99344583	99416811	29	35 626	0.848	0.126
SCN3A	6 328	2	165934030	166095577	207	37 801	0.626	0.161
AKR1C4	1 109	10	5203798	5270910	67	37 208	0.605	0.174
SCN2A	6 326	2	165951659	166258820	558	37 979	0.252	0.240
AKR1C3	8 644	10	5055958	5159878	99	37 111	0.341	0.246
CBR3	874	21	37471614	37528860	171	37 292	0.158	0.301
ALB	213	4	74234972	74297129	108	37 318	0.187	0.304
ABCB1	5 243	7	87123179	87377639	361	37 714	-0.123	0.390
SCN2B	6 327	11	118023519	118082337	120	37 475	-0.181	0.431
AKR1C1	1 645	10	4970454	5030158	101	37 608	-0.233	0.458
SCN4A	6 329	17	62005914	62101876	44	37 450	-0.487	0.560
AKR1C2	1 646	10	5019967	5095225	2	36 830	-0.477	0.569
CYP3A5	1 577	7	99235813	99312636	65	37 588	-0.823	0.706
CBR1	873	21	37407285	37455462	120	37 458	-0.993	0.736
SCN4B	6 330	11	117994092	118058630	91	37 352	-1.004	0.742
SCN8A	6 334	12	51949050	52216648	272	37 199	-1.788	0.926

靶基因	靶基因ID	染色体位置	起始位置	终止位置	SNP数量	样本量	P值相关统计量	P
SCN1A	6 323	2	166835670	167040642	507	38 017	6.025	< 0.001
SCN9A	6 335	2	167041695	167267497	519	37 621	3.253	< 0.001
SCN7A	6 332	2	167250083	167378481	268	37 555	1.793	0.015
SCN3B	55 800	11	123489895	123560315	185	37 870	1.742	0.017
SCN11A	11 280	3	38877260	39030136	283	38 190	1.441	0.036
SCN10A	6 336	3	38728837	38870501	328	37 505	1.231	0.049
SCN1B	6 324	19	35486555	35541353	10	35 245	1.053	0.085
CYP2C19	1 557	10	96487463	96622671	285	38 149	1.020	0.090
SCN5A	6 331	3	38579553	38726164	242	37 201	0.788	0.103
CYP3A4	1 576	7	99344583	99416811	29	35 626	0.848	0.126
SCN3A	6 328	2	165934030	166095577	207	37 801	0.626	0.161
AKR1C4	1 109	10	5203798	5270910	67	37 208	0.605	0.174
SCN2A	6 326	2	165951659	166258820	558	37 979	0.252	0.240
AKR1C3	8 644	10	5055958	5159878	99	37 111	0.341	0.246
CBR3	874	21	37471614	37528860	171	37 292	0.158	0.301
ALB	213	4	74234972	74297129	108	37 318	0.187	0.304
ABCB1	5 243	7	87123179	87377639	361	37 714	-0.123	0.390
SCN2B	6 327	11	118023519	118082337	120	37 475	-0.181	0.431
AKR1C1	1 645	10	4970454	5030158	101	37 608	-0.233	0.458
SCN4A	6 329	17	62005914	62101876	44	37 450	-0.487	0.560
AKR1C2	1 646	10	5019967	5095225	2	36 830	-0.477	0.569
CYP3A5	1 577	7	99235813	99312636	65	37 588	-0.823	0.706
CBR1	873	21	37407285	37455462	120	37 458	-0.993	0.736
SCN4B	6 330	11	117994092	118058630	91	37 352	-1.004	0.742
SCN8A	6 334	12	51949050	52216648	272	37 199	-1.788	0.926

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