HRAS基因单核苷酸多态性与精神分裂症及非典型抗精神病药物疗效的关联研究

doi:10.3969/j.issn.1674-8115.2021.12.010

上海交通大学学报(医学版) ›› 2021, Vol. 41 ›› Issue (12): 1613-1617.doi: 10.3969/j.issn.1674-8115.2021.12.010

• 论著 · 基础研究 • 上一篇

HRAS基因单核苷酸多态性与精神分裂症及非典型抗精神病药物疗效的关联研究

李睿¹(), 曾端¹, 和申¹, 沈一峰¹, 李华芳¹^,²^,³()

^1.上海交通大学医学院附属精神卫生中心精神科，上海 200030
^2.上海市精神心理疾病临床医学研究中心，上海 200030
^3.上海市重性精神病重点实验室，上海 200030

收稿日期:2021-05-13 出版日期:2021-12-28 发布日期:2022-01-28
通讯作者: 李华芳 E-mail:18351998232@163.com;lhlh-5@163.com
作者简介:李睿（1996—），女，硕士生；电子信箱：18351998232@163.com。
基金资助:
上海市精神心理疾病临床医学研究中心项目(19MC1911100);上海交通大学医工交叉研究基金(YG2017MS42);上海市转化医学协同创新中心项目(TM201727);上海交通大学医学院博士创新基金项目(BXJ201955);上海市公共卫生优秀青年人才培养计划(GWV-10.2-YQ45)

Association study of HRAS proto-oncogene single nucleotide polymorphism with schizophrenia and therapeutic response to atypical antipsychotics

Rui LI¹(), Duan ZENG¹, Shen HE¹, Yi-feng SHEN¹, Hua-fang LI¹^,²^,³()

^1.Department of Psychiatry, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China
^2.Shanghai Clinical Research Center for Mental Health, Shanghai 200030, China
^3.Shanghai Key Laboratory of Psychotic Disorders, Shanghai 200030, China

Received:2021-05-13 Online:2021-12-28 Published:2022-01-28
Contact: Hua-fang LI E-mail:18351998232@163.com;lhlh-5@163.com
Supported by:
Project of Shanghai Clinical Research Center for Mental Health(19MC1911100);Shanghai Jiao Tong University Interdisciplinary Research Grant(YG2017MS42);Shanghai Collaborative Innovation Center for Translational Medicine(TM201727);Innovation Program for Ph.D. Students in Shanghai Jiao Tong University School of Medicine(BXJ201955);Shanghai Outstanding Youth Training Program in Public Health(GWV-10.2-YQ45)

摘要/Abstract

摘要：

目的·探讨中国汉族人群精神分裂症患者HRAS原癌基因（HRAS proto-oncogene，HRAS）rs11246176位点多态性与精神分裂症及非典型抗精神病药物疗效的相关性。方法·纳入460例急性发作期精神分裂症患者（病例组）及386名健康对照者（对照组）。精神分裂症患者均予以非典型抗精神病药物治疗，并完成26周随访。采用阳性和阴性症状量表（Positive and Negative Syndrome Scale，PANSS）分别于入组时、入组13周和入组26周评定患者情况，计算26周时的减分率作为评定药物疗效的标准（减分率≥50%为有效，<50%为无效），据此将患者分为有效组和无效组。采集所有对象的外周静脉血，提取DNA，采用TaqMan探针基因分型技术对HRAS基因rs11246176位点进行基因分型，应用SHEsis和SNPstats软件比较病例组与对照组、有效组与无效组等位基因和基因型频率分布差异以及不同遗传模式下基因型频率分布差异。采用表达数量性状基因座（expression quantitative trait loci，eQTL）关联分析探讨rs11246176位点多态性与人脑内HRAS基因表达的关系。结果·rs11246176等位基因及基因型频率在病例组与对照组间的差异无统计学意义（均P>0.05）。有效组中A等位基因频率高于无效组，差异有统计学意义（P＝0.010）；有效组A等位基因携带者（AA+AG基因型）频率高于无效组，差异有统计学意义（P＝0.040）。另外，rs11246176位点A等位基因携带者在26周时的PANSS减分率显著高于GG基因型（P=0.010）。eQTL分析发现正常高加索人和非裔美国人背外侧前额叶皮层rs11246176 位点AA基因型的HRAS mRNA表达水平最高，其次为AG型，GG型表达水平最低（P=0.000）。结论·HRAS基因rs11246176位点可能与中国汉族人群精神分裂症的发生无关，但可能与非典型抗精神病药物的疗效有关，非典型抗精神病药物可能对A等位基因携带患者的疗效较好。

关键词: 精神分裂症, HRAS原癌基因, 单核苷酸多态性, rs11246176位点, 非典型抗精神病药

Abstract:

Objective·To investigate the relation of HRAS proto-oncogene (HRAS) polymorphism in rs11246176 with schizophrenia and therapeutic response to atypical antipsychotics in the Chinese Han population.

Methods·A total of 460 schizophrenia patients with acute attack (case group) and 386 healthy controls (control group) were recruited. The patients were treated with atypical antipsychotics and followed up for 26 weeks. Positive and Negative Syndrome Scale (PANSS) were used to evaluate the patients' conditions at the time of enrollment, and 13 weeks and 26 weeks after enrollment respectively. The reduction rates at 26th week were calculated as the standard for drug efficacy (the reduction rate ≥50% was considered effective, and <50% was considered ineffective), and then the patients were divided into the responder group and the non-responder group. The peripheral blood samples were collected to extract DNA. Rs11246176 was genotyped by using TaqMan assays. SHEsis software and SNPstats software were used to compare the frequency distributions of alleles, genotypes, and genotypes under different genetic models between the case group and the control group as well as between the responder group and the non-responder group. In addition, expression quantitative trait loci (eQTL) analysis was used to explore the difference in HRAS expression in the brain among different rs11246176 genotypes.

Results·There were no significant differences in the distribution of allelic and genotypic frequencies between the case group and the control group (P>0.05). The frequency of A allele in the responder group was higher than that in the non-responder group (P=0.010). The frequency of AA and AG genotypes in the responder group was higher than that in the non-responder group (P=0.040). The reduction rate of PANSS of the patients with AA or AG genotype 26th week was significantly higher than that of the patients with GG genotype (P=0.010). Furthermore, the brain eQTL analysis revealed that in the dorsolateral prefrontal cortex of normal Caucasians and African Americans, the HRAS mRNA expression level of the AA genotype was the highest, followed by the AG genotype and the GG genotype in the order (P=0.000).

Conclusion·Rs11246176 polymorphism in HRAS gene is not associated with the occurrence of schizophrenia in the Chinese Han population, but may be related to therapeutic response to atypical antipsychotics. A allele carriers may have better response to atypical antipsychotics.

Key words: schizophrenia, HRAS proto-oncogene, single nucleotide polymorphism (SNP), rs11246176, atypical antipsychotics

中图分类号:

R749.3

李睿, 曾端, 和申, 沈一峰, 李华芳. HRAS基因单核苷酸多态性与精神分裂症及非典型抗精神病药物疗效的关联研究[J]. 上海交通大学学报(医学版), 2021, 41(12): 1613-1617.

Rui LI, Duan ZENG, Shen HE, Yi-feng SHEN, Hua-fang LI. Association study of HRAS proto-oncogene single nucleotide polymorphism with schizophrenia and therapeutic response to atypical antipsychotics[J]. JOURNAL OF SHANGHAI JIAOTONG UNIVERSITY (MEDICAL SCIENCE), 2021, 41(12): 1613-1617.

图/表 5

参考文献 24

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Index	Responder group （n=132）	Non-responder group （n=323）	P value
Age/year	48.19±17.26	48.75±13.11	0.741
Male/female/n	63/69	155/168	0.960
Baseline PANSS score/score	77.84±16.13	74.25±15.35	0.071
Onset age/year	26.42±10.18	27.24±11.29	0.474
Disease course/year	18 （5‒32）	21 （8‒33）	0.171
Drug dosage^①/（mg·d^-1）	10.0 （5.0‒15.0）	10.0 （5.0‒14.4）	0.469
Baseline application of drug （users/non-users）/n	97/35	217/106	0.187

Index	Responder group （n=132）	Non-responder group （n=323）	P value
Age/year	48.19±17.26	48.75±13.11	0.741
Male/female/n	63/69	155/168	0.960
Baseline PANSS score/score	77.84±16.13	74.25±15.35	0.071
Onset age/year	26.42±10.18	27.24±11.29	0.474
Disease course/year	18 （5‒32）	21 （8‒33）	0.171
Drug dosage^①/（mg·d^-1）	10.0 （5.0‒15.0）	10.0 （5.0‒14.4）	0.469
Baseline application of drug （users/non-users）/n	97/35	217/106	0.187

Group	Allele/n（%）		χ² value	P value	Genotype/n（%）			χ² value	P value
Group	A	G	χ² value	P value	AA	AG	GG	χ² value	P value
Case group	138 （15.2）	772 （84.8）	0.172	0.400	13 （2.9）	112 （24.6）	330 （72.5）	1.008	0.600
Control group	105 （13.7）	661 （86.3）			11 （2.9）	83 （21.7）	289 （75.5）
Responder group	52 （19.7）	212 （80.3）	5.943	0.010	7 （5.3）	38 （28.8）	87 （65.9）	6.332	0.040
Non-responder group	86 （13.3）	560 （86.7）			6 （1.9）	74 （22.9）	243 （75.2）

Group	Allele/n（%）		χ² value	P value	Genotype/n（%）			χ² value	P value
Group	A	G	χ² value	P value	AA	AG	GG	χ² value	P value
Case group	138 （15.2）	772 （84.8）	0.172	0.400	13 （2.9）	112 （24.6）	330 （72.5）	1.008	0.600
Control group	105 （13.7）	661 （86.3）			11 （2.9）	83 （21.7）	289 （75.5）
Responder group	52 （19.7）	212 （80.3）	5.943	0.010	7 （5.3）	38 （28.8）	87 （65.9）	6.332	0.040
Non-responder group	86 （13.3）	560 （86.7）			6 （1.9）	74 （22.9）	243 （75.2）

Model	OR	95%CI	P value
Codominant			0.670
GG	1.00
AG	0.85	0.56‒1.28
AA	1.20	0.41‒3.47
Dominant			0.520
GG	1.00
AG/AA	0.88	0.59‒1.31
Recessive			0.680
GG/AG	1.00
AA	1.25	0.43‒3.61
Log-additive	0.93	0.66‒1.31	0.680

HRAS基因单核苷酸多态性与精神分裂症及非典型抗精神病药物疗效的关联研究

Association study of HRAS proto-oncogene single nucleotide polymorphism with schizophrenia and therapeutic response to atypical antipsychotics

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Metrics

Time	PANSS total score/score			Reduction rate of total score/%			P_AA+AG/GG^①	P_AA/AG+GG^②
Time	AA	AG	GG	AA	AG	GG	P_AA+AG/GG^①	P_AA/AG+GG^②
Baseline	73.08±10.00	76.47±11.71	75.08±13.28	‒	‒	‒
13 weeks	57.46±13.75	58.38±15.48	55.15±15.56	37.01±23.94	35.39±40.17	31.06±41.33	0.293	0.672
26 weeks	55.15±15.56	61.63±17.93	64.23±17.11	42.09±33.87	30.99±33.65	22.70±34.84	0.010	0.077

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