HBV前C、C、BCP区位点变异与中医证型的相关性分析

尚东方; 王世雷; 赵文霞

doi:10.3969/j.issn.1001-5256.2021.04.017

HBV前C、C、BCP区位点变异与中医证型的相关性分析

DOI: 10.3969/j.issn.1001-5256.2021.04.017

1.
河南中医药大学研究生院, 郑州 450000
2.
河南中医药大学第一附属医院脾胃肝胆科, 郑州 450000

基金项目:

国家自然科学基金面上项目 (81473651);

河南省中医药科学研究专项 (2018JDZX005);

国家中医药管理局全国名老中医药专家传承工作室建设项目 (国中医药人教函〔2018〕134号)

利益冲突声明：本研究不存在研究者、伦理委员会成员、受试者监护人以及与公开研究成果有关的利益冲突。

作者贡献声明：尚东方、王世雷负责收集、分析资料及数据，撰写论文；赵文霞负责课题设计，拟定写作思路，指导撰写文章并最后定稿。

详细信息

作者简介:
尚东方(1989—)，女，在读博士，主要从事脾胃肝胆病的研究

通信作者:
赵文霞，zhaowenxia@163.com

中图分类号: R512.62
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- 被引次数: 0
出版历程
- 收稿日期: 2020-09-14
- 录用日期: 2020-11-25
- 出版日期: 2021-04-20

Association of gene mutations in the pre-C, C, and basic core promoter regions of hepatitis B virus with traditional Chinese medicine syndrome types

1.
Graduate School, Henan University of Chinese Medicine, Zhengzhou 450000, China
2.
Department of Hepatology and Spleen-Stomach, The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou 450000, China

摘要

摘要: 目的探讨慢性乙型肝炎(CHB)患者HBV的前C区、C区、基本核心启动子(BCP)区位点变异与中医证型的相关性。方法回顾性分析2014年11月—2018年6月于河南中医药大学第一附属医院脾胃肝胆科门诊及病房诊治的CHB患者临床资料。收集并记录患者的基本情况、HBV血清学指标、HBV各位点变异情况及中医四诊信息，参照病毒性肝炎的中医辨证标准，对各病例进行辨证分型，继而分析HBV前C、C、BCP区位点变异与中医证型的相关性。计数资料组间比较采用χ²检验；计量资料多组之间及两两比较采用Kruskal-Wallis H检验。结果纳入235例CHB患者中，湿热内结证101例，肝郁脾虚证88例，瘀血阻络证17例，肝肾阴虚证19例，脾肾阳虚证10例。性别、年龄、病程在不同中医证型中存在显著差异(χ²=17.389、H=173.280、H=86.520，P值均＜0.01)。CHB患者年龄在HBV前C、C、BCP区位点变异间差异有统计学意义(H=30.150，P＜0.001)。HBV前C、C、BCP区变异的CHB患者其中医证型分布存在显著差异(χ²=58.117，P＜0.001)，主要证型为湿热内结证和肝郁脾虚证，两证型所占比例为80.43%。湿热内结证易出现A1762T、G1764A位点变异，肝郁脾虚证易出现G1896A、A1762T、G1764A位点变异，瘀血阻络证和肝肾阴虚证均易出现G1764A位点变异，脾肾阳虚证易出现I97L位点变异。结论 CHB患者HBV前C、C、BCP区位点变异与中医证型存在一定的关联性，湿热内结证及肝郁脾虚证最常见，脾肾阳虚证易发生I97L位点变异。
- 乙型肝炎, 慢性 /
- 点突变 /
- 证候 /
- 中医学
Abstract: Objective To investigate the association of gene mutations in the pre-C, C, and basic core promoter (BCP) regions of hepatitis B virus (HBV) with traditional Chinese medicine (TCM) syndrome types in patients with chronic hepatitis B (CHB). Methods A retrospective analysis was performed for the clinical data of CHB patients who were diagnosed and treated at the outpatient service and ward of Spleen, Stomach, and Hepatobiliary Department, The First Affiliated Hospital of Henan University of Chinese Medicine, from November 2014 to June 2018. Related clinical data were collected and recorded, including general information, HBV serological markers, HBV gene mutations, and information obtained by four TCM diagnostic methods. Syndrome differentiation and typing were performed for each patient with reference to the criteria for TCM syndrome differentiation of viral hepatitis, and the association of gene mutation in the pre-C, C, and BCP regions of HBV with TCM syndrome types was analyzed. The chi-square test was used for comparison of categorical data between groups, and the Kruskal-Wallis H test was used for comparison of continuous data between multiple or two groups. Results A total of 235 patients with CHB were enrolled, among whom 101 had internal retention of damp-heat, 88 had stagnation of liver Qi and spleen deficiency, 17 had blood stasis obstructing the collaterals, 19 had liver-kidney Yin deficiency, and 10 had spleen-kidney Yang deficiency. There were significant differences in sex, age, and course of disease between the patients with different TCM syndrome types (χ²=17.389, H=173.280, H=86.520, all P < 0.01), and there was a significant difference in age between the CHB patients with gene mutations in the pre-C, C and BCP regions of HBV (H=30.150, P < 0.001). There was a significant difference in the distribution of TCM syndrome types between the CHB patients with gene mutations in the pre-C, C and BCP regions of HBV (χ²=58.117, P < 0.001), and internal retention of damp-heat and stagnation of liver Qi and spleen deficiency were major TCM syndrome types accounting for 80.43%. The patients with internal retention of damp-heat tended to have A1762T and G1764A mutations, and those with stagnation of liver Qi and spleen deficiency tended to have G1896A, A1762T, and G1764A mutations; G1764A mutation was often observed in the patients with blood stasis obstructing the collaterals or liver-kidney Yin deficiency, and I97L mutation was often observed in the patients with spleen-kidney Yang deficiency. Conclusion Gene mutations in the pre-C, C, and BCP regions of HBV are associated with TCM syndrome types in CHB patients, and internal retention of damp-heat and stagnation of liver Qi and spleen deficiency are the most common TCM syndrome types. I97L mutation is often observed in patients with spleen-kidney Yang deficiency.
- Hepatitis B, Chronic /
- Point Mutation /
- Symptom Complex /
- TCM Science

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表 1 CHB中医证型与性别、家族史、年龄、病程的关系

指标	湿热内结证(n=101)	肝郁脾虚证(n=88)	瘀血阻络证(n=17)	肝肾阴虚证(n=19)	脾肾阳虚证(n=10)	统计值	P值
性别(例)						χ²=17.389	0.002
男	59	71	7	6	8
女	21	35	11	13	4
家族史(例)						χ²=0.229	0.994
有	49	67	12	11	8
无	31	39	6	7	5
年龄(岁)	34.9±4.5	42.3±5.9¹⁾	55.5±6.6¹⁾²⁾	52.4±6.9¹⁾²⁾	51.5±8.4¹⁾²⁾	H=173.280	＜0.001
病程(年)	10.2±4.5	13.6±4.1¹⁾	18.2±4.0¹⁾²⁾	17.5±3.3¹⁾²⁾	15.1±3.5¹⁾²⁾	H=86.520	＜0.001
注：与湿热内结证相比，1)P＜0.01，与肝郁脾虚证相比，2)P＜0.05。

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表 2 HBV前C、C、BCP区位点变异与性别、年龄及病程之间的关系

HBV变异类型	例数	性别(例)		年龄(岁)	病程(年)
HBV变异类型	例数	男	女	年龄(岁)	病程(年)
前C区变异	24	15	9	41.8±6.9	13.8±3.7
C区变异	18	9	9	46.8±8.0	14.5±4.2
BCP区变异	52	39	13	39.9±9.0¹⁾	12.5±5.0
前C、C区双变异	26	19	7	40.1±7.2	12.8±4.5
C、BCP区双变异	33	22	11	40.6±9.2	11.6±5.2
前C、BCP区双变异	45	30	15	40.3±8.5	12.5±5.1
前C、C、BCP区联合变异	37	25	12	40.4±8.9	12.7±5.1
统计值		χ²=4.522		H=30.150	H=10.707
P值		0.606		＜0.001	0.152
注：与C区变异相比，1)P＜0.05。

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表 3 HBV前C、C、BCP区位点变异和中医证型关系

HBV变异类型	湿热内结证(例)	肝郁脾虚证(例)	瘀血阻络证(例)	肝肾阴虚证(例)	脾肾阳虚证(例)
前C区变异	2	18	2	2	0
C区变异	2	7	3	2	4
BCP区变异	34	10	3	5	0
前C、C区双变异	7	14	2	2	1
C、BCP区双变异	16	13	1	2	1
前C、BCP区双变异	22	15	4	2	2
前C、C、BCP区联合变异	18	11	2	4	2

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表 4 HBV各变异位点分布情况

变异位点	湿热内结证	肝郁脾虚证	瘀血阻络证	肝肾阴虚证	脾肾阳虚证
A1762T[例(%)]	82(81.2)	44(50.0)	7(41.2)	9(47.3)	3(30.0)
G1764A[例(%)]	83(82.2)	46(52.3)	8(47.0)	10(52.6)	4(40.0)
G1862T[例(%)]	15(14.9)	14(15.9)	2(11.8)	3(15.8)	2(20.0)
G1896A[例(%)]	30(29.7)	45(51.1)	7(41.2)	7(36.8)	4(40.0)
G1899A[例(%)]	14(13.9)	15(17.0)	3(17.6)	2(10.5)	2(20.0)
L60V[例(%)]	6(5.9)	7(8.0)	3(17.6)	3(15.8)	1(10.0)
S87G[例(%)]	16(15.8)	17(19.3)	2(11.8)	2(10.5)	2(20.0)
I97L[例(%)]	32(34.6)	34(38.6)	5(29.4)	7(36.8)	6(60.0)

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参考文献(14)

[1]	LOZANO R, NAGHAVI M, FOREMAN K, et al. Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: A systematic analysis for the Global Burden of Disease Study 2010[J]. Lancet, 2012, 380(9859): 2095-2128. DOI: 10.1016/S0140-6736(12)61728-0
[2]	GOLDSTEIN ST, ZHOU F, HADLER SC, et al. A mathematical model to estimate global hepatitis B disease burden and vaccination impact[J]. Int J Epidemiol, 2005, 34(6): 1329-1339. DOI: 10.1093/ije/dyi206
[3]	WANG FS, FAN JG, ZHANG Z, et al. The global burden of liver disease: The major impact of China[J]. Hepatology, 2014, 60(6): 2099-2108. DOI: 10.1002/hep.27406
[4]	XIAO Q, TAN SZ, SHEN JJ. Correlation of liver stagnation and spleen deficiency syndrome with HBV genetype and genovariation in chronic hepatitis B patients of HBeAg in negative[J]. J Tradit Chin Med, 2011, 52(2): 136-138. (in Chinese) https://www.cnki.com.cn/Article/CJFDTOTAL-ZZYZ201102019.htm 肖倩, 谭善忠, 沈建军. 慢性乙型肝炎e抗原阴性患者肝郁脾虚证与HBV基因型和基因变异类型的相关性[J]. 中医杂志, 2011, 52(2): 136-138. https://www.cnki.com.cn/Article/CJFDTOTAL-ZZYZ201102019.htm
[5]	ZHOU F, WANG LT, CHEN JJ, et al. Relationship between basal core promoter combined point mutation of hepatitis B virus and TCM syndrome[J]. Chin J Integr Trad West Med, 2005, 25(9): 777-779. (in Chinese) https://www.cnki.com.cn/Article/CJFDTOTAL-ZZXJ200509003.htm 周飞, 王灵台, 陈建杰, 等. 乙型肝炎病毒BCP联合点突变与中医证型的关系[J]. 中国中西医结合杂志, 2005, 25(9): 777-779. https://www.cnki.com.cn/Article/CJFDTOTAL-ZZXJ200509003.htm
[6]	Chinese Society of Hepatology and Chinese Society of Infectious Diseases, Chinese Medical Association. The guideline of prevention andtreatment for chronic hepatitis B: A 2015 update[J]. J Clin Hepatol, 2015, 31(12): 1941-1960. (in Chinese) DOI: 10.3969/j.issn.1001-5256.2015.12.002 中华医学会肝病学分会, 中华医学会感染病学分会. 慢性乙型肝炎防治指南(2015年更新版)[J]. 临床肝胆病杂志, 2015, 31(12): 1941-1960. DOI: 10.3969/j.issn.1001-5256.2015.12.002
[7]	Branch of Hepatobiliary Diseases, Chinese Association of Chinese Medicine. The standards of traditional Chinese medicine syndrome differentiation for viral Hepatitis[J]. J Clin Hepatol, 2017, 33(10): 1839 -1846. (in Chinese) DOI: 10.3969/j.issn.1001-5256.2017.10.002 中华中医药学会肝胆病分会. 病毒性肝炎中医辨证标准[J]. 临床肝胆病杂志, 2017, 33(10): 1839 -1846. DOI: 10.3969/j.issn.1001-5256.2017.10.002
[8]	YIN YH, YI ZJ, JIN YQ. Thoughts on in-depth study of TCM syndrome genomics[J]. Hunan J Tradit Chin Med, 2006, 22(6): 1-2. (in Chinese) https://www.cnki.com.cn/Article/CJFDTOTAL-HNZO200606000.htm 尹耀慧, 易振佳, 金益强. 证候基因组学深入研究的思考[J]. 湖南中医杂志, 2006, 22(6): 1-2. https://www.cnki.com.cn/Article/CJFDTOTAL-HNZO200606000.htm
[9]	LEI CG, QIN JF, CAI L. Correlation between TCM syndrome types and clinical test indexes of chronic hepatitis B[J]. Chin J Basic Med Tradit Chin Med, 2017, 23(3): 357-358. (in Chinese) https://www.cnki.com.cn/Article/CJFDTOTAL-ZYJC201703026.htm 雷长国, 覃建锋, 蔡林. 慢性乙型肝炎中医证型与临床检验指标相关性研究[J]. 中国中医基础医学杂志, 2017, 23(3): 357-358. https://www.cnki.com.cn/Article/CJFDTOTAL-ZYJC201703026.htm
[10]	LIU EL, WANG XJ. Correlation between distribution of TCM syndromes and clinical test indicators based on 451 cases chronic viral hepatitis type B[J]. China J Tradit Chin Med Pharma, 2019, 34(4): 1793-1795. (in Chinese) https://www.cnki.com.cn/Article/CJFDTOTAL-BXYY201904131.htm 刘二丽, 汪晓军. 451例慢性乙型病毒性肝炎患者中医证型分布及与临床检验指标的相关性[J]. 中华中医药杂志, 2019, 34(4): 1793-1795. https://www.cnki.com.cn/Article/CJFDTOTAL-BXYY201904131.htm
[11]	WANG Y. Effect of hepatitis B virus basal core promoter mutations on the transcriptional cis-activating function and virus replication capacity[D]. Hohhot: Agricultural University of The Inner Mongol, 2010. (in Chinese) 王耀. 乙型肝炎病毒基本核心启动子变异对启动子活性及病毒复制力影响的研究[D]. 呼和浩特: 内蒙古农业大学, 2010.
[12]	WU XF, WANG HY, ZHOU BQ, et al. Clinical research of the relationship between mutations of hepatitis B virus precore and the core promoter gene and HBV DNA concentration[J]. Chin J Gastroenterol Hepatol, 2007, 16(5): 401-403. (in Chinese) https://www.cnki.com.cn/Article/CJFDTOTAL-WCBX200705002.htm 吴小飞, 王华雨, 周宝勤, 等. 乙型肝炎病毒前C基因区变异与乙肝病毒复制关系的临床研究[J]. 胃肠病学和肝病学杂志, 2007, 16(5): 401-403. https://www.cnki.com.cn/Article/CJFDTOTAL-WCBX200705002.htm
[13]	YAN J, YAO Z, HU K, et al. Hepatitis B virus core promoter A1762T/G1764A (TA)/T1753A/T1768A mutations contribute to hepatocarcinogenesis by deregulating Skp2 and P53[J]. Dig Dis Sci, 2015, 60(5): 1315-1324. DOI: 10.1007/s10620-014-3492-9
[14]	CUI XJ, CHO YK, SONG BC. Influence of the basal core promoter and precore mutation on replication of hepatitis B virus and antiviral susceptibility of different genotypes[J]. J Med Virol, 2015, 87(4): 601 -608. DOI: 10.1002/jmv.24117