三七总皂苷编码基因治疗急性心肌梗死的潜在分子靶向策略研究

周瑞玲; 孙敬辉; 邓艳萍; 黄弘博; 牛泽龙; 王培利

doi:10.16766/j.cnki.issn.1674-4152.004198

三七总皂苷编码基因治疗急性心肌梗死的潜在分子靶向策略研究

doi: 10.16766/j.cnki.issn.1674-4152.004198

1.
中国中医科学院西苑医院国家中医心血管病医学研究中心，北京 100091
2.
北京中医药大学研究生院，北京 100029

基金项目:

国家自然科学基金项目 82305028

详细信息

通讯作者:
王培利，E-mail：191593690@qq.com

中图分类号: R542.22
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出版历程
- 收稿日期: 2025-01-10

Exploring potential molecular targeting strategies for the treatment of acute myocardial infarction with genes encoding panax notoginseng saponins

1.
National Research Center of Chinese Medicine and Cardiovascular Diseases, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing 100091, China

摘要

摘要: 目的利用孟德尔随机化方法(MR)分析三七总皂苷(PNS)抗血栓药物靶点的遗传基因与急性心肌梗死(AMI)的因果关系。方法从欧洲生物信息研究所、芬兰数据库、UK Biobank数据库得到全基因组关联研究(GWAS)数据集，均可在IEU Open GWAS网站在线获取。以随机效应逆方差加权法为主分析方法，MR-Egger回归检验水平多效性，Cochran' s Q检验评估异质性，留一法敏感性分析评估稳定性。结果共获取18个PNS核心靶点，将18个靶点的遗传代理经血栓类阳性疾病筛选后确定11个有效的抗血栓靶点，最终产生5个治疗AMI的潜在靶点，包括HIF1A、MDM2、CCND1、TP53、INS。PNS靶标HIF1A、CCND1、TP53、INS与AMI发生风险增加相关(均OR>1, P<0.05)，MDM2与AMI发生风险降低相关(OR=0.671, P=0.022)。结论 PNS具有潜在的治疗作用，可通过抗血栓基因靶向心肌凋亡通路调控AMI进展，为AMI精准治疗策略开发提供了关键靶点。
- 急性心肌梗死 /
- 三七总皂苷 /
- 药靶孟德尔 /
- 分子靶向
Abstract: Objective To analyze the causal relationship between genes underlying the antithrombotic drug target of Panax notoginseng saponins (PNS) and acute myocardial infarction (AMI) using Mendelian randomization (MR) method. Methods Genome-wide association study (GWAS) datasets were obtained from the European Bioinformatics Institute, Finnish database and UK Biobank database, all available online at the IEU Open GWAS website. Random-effects inverse variance weighting was the main analytical method, MR-Egger regression tested for horizontal pleiotropy, Cochran' s Q test assessed heterogeneity, and leave-one-out sensitivity analysis assessed stability. Results Eighteen core drug targets of PNS were obtained, and the genetic proxies of the 18 targets were screened for thrombus-positive diseases to identify 11 effective antithrombotic targets, which resulted in five potential drug targets for the treatment of AMI, including HIF1A, MDM2, CCND1, TP53 and INS. PNS targets HIF1A, CCND1, TP53, and INS were associated with an increased risk of AMI (all OR>1, P<0.05), and MDM2 was associated with a decreased risk of AMI (OR=0.671, P=0.022). Conclusion PNS exhibits potential therapeutic effects for AMI by targeting myocardial apoptosis pathways through antithrombotic genes to modulate disease progression, highlighting its potential as a key target for developing precision therapeutic strategies.
- Acute myocardial infarction /
- Panax notoginseng saponins /
- Drug-targeted Mendelian /
- Molecular targeting
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图 1 PNS的18个核心靶点

Figure 1. Eighteen core targets identified for PNS

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表 1 各种表型的GWAS数据集信息

Table 1. GWAS dataset information for each phenotype

暴露/结局	GWAS ID	样本量(病例/对照)	SNP数量
血小板计数	ebi-a-GCST90002357	542 827	46 393 493
静脉血栓栓塞症	finn-b-I9_VTE	9 176/209 616	16 380 466
动脉栓塞和血栓形成	finn-b-I9_ARTEMBTHR	789/206 541	16 380 409
肺栓塞	finn-b-I9_PULMEMB	4 185/214 228	16 380 466
其他栓塞和血栓形成	finn-b-I9_THROMBOTH	1 919/190 028	16 380 403
急性心肌梗死	ukb-a-533	3 927/333 272	10 894 596
急性心肌梗死	ukb-e-I21_CSA	374/8 502	9 805 094

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表 2 PNS靶标与静脉血栓栓塞症(finn-b-I9_VTE)的MR结果

Table 2. MR analysis of PNS targets on venous thromboembolism (finn-b-I9_ARTEMBTHR)

靶点	随机效应逆方差加权法				多效性检验MR-Egger
靶点	SNP数量	效应值β	SE	P值	截距	SE	P值
HIF1A	243	-0.231	0.071	0.001	-0.001	0.004	0.858
MDM2	407	0.307	0.035	<0.001	0.002	0.003	0.518
AKT1	12	-0.651	0.270	0.016	-0.028	0.020	0.188
CCND1	220	0.325	0.074	<0.001	0.000	0.003	0.963
TP53	295	0.360	0.058	<0.001	0.000	0.003	0.949
CTNNB1	547	0.192	0.044	<0.001	-0.001	0.002	0.521
INS	461	0.233	0.067	<0.001	0.000	0.003	0.893

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表 3 PNS靶标与动脉栓塞和血栓形成(finn-b-I9_ARTEMBTHR)的MR结果

Table 3. MR results of PNS targets on arterial embolism and thrombosis (finn-b-I9_ARTEMBTHR)

靶点	随机效应逆方差加权法				多效性检验MR-Egger
靶点	SNP数量	效应值β	SE	P值	截距	SE	P值
MDM2	407	0.441	0.100	<0.001	-0.012	0.007	0.095
CDKN1A	239	0.435	0.150	0.004	-0.003	0.008	0.651
MYC	65	-0.805	0.395	0.041	0.010	0.024	0.668
AKT1	12	2.454	0.828	0.003	-0.030	0.063	0.644
CTNNB1	547	-0.232	0.113	0.040	-0.002	0.006	0.662
ESR1	20	1.242	0.575	0.031	-0.011	0.044	0.806
EP300	106	-0.516	0.246	0.036	0.009	0.012	0.446

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表 4 PNS靶标与肺栓塞(finn-b-I9_PULMEMB)的MR结果

Table 4. The MR results of PNS target on pulmonary embolism (finn-b-I9_PULMEMB)

靶点	随机效应逆方差加权法				多效性检验MR-Egger
靶点	SNP数量	效应值β	SE	P值	截距	SE	P值
HIF1A	243	-0.274	0.095	0.004	0.002	0.005	0.645
MDM2	407	0.093	0.043	0.032	0.006	0.003	0.093
CCND1	220	0.523	0.103	<0.001	0.002	0.005	0.734
TP53	295	0.452	0.085	<0.001	-0.004	0.004	0.283
CTNNB1	547	0.284	0.060	<0.001	-0.001	0.003	0.679
INS	461	0.401	0.081	<0.001	0.001	0.004	0.763
ESR1	20	0.532	0.233	0.023	0.012	0.020	0.556

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表 5 PNS靶标与其他栓塞和血栓形成(finn-b-I9_THROMBOTH)的MR结果

Table 5. MR results of PNS targets in relation to other embolisms and thromboses (finn-b-I9_THROMBOTH)

靶点	随机效应逆方差加权法				多效性检验MR-Egger
靶点	SNP数量	效应值β	SE	P值	截距	SE	P值
HIF1A	243	0.253	0.109	0.020	-0.001	0.007	0.904
MDM2	407	0.269	0.063	<0.001	-0.008	0.005	0.100
MYC	65	-0.638	0.267	0.017	-0.031	0.016	0.051
AKT1	12	1.224	0.540	0.023	0.008	0.040	0.843
TP53	295	0.279	0.123	0.023	0.003	0.006	0.636
CTNNB1	547	0.166	0.079	0.035	0.000	0.004	0.987
INS	461	1.046	0.150	<0.001	0.008	0.007	0.282
EP300	106	-0.767	0.139	<0.001	0.007	0.008	0.379

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表 6 PNS抗血栓有效靶点与急性心肌梗死(ukb-e-I21_CSA; ukb-a-533)AMI有因果关系的5个靶点

Table 6. The 5 causal targets of PNS (Panax notoginseng saponins) against thrombosis in relation to acute myocardial infarction (AMI; ukb-e-I21_CSA; ukb-a-533)

靶点	随机效应逆方差加权法					多效性检验MR-Egger
靶点	SNP数量	效应值β	SE	P值	OR(95% CI)	截距	SE	P值
HIF1A	244	0.926	0.302	0.002	2.525(1.398~4.560)	0.006	0.017	0.733
MDM2	302	-0.399	0.174	0.022	0.671(0.478~0.943)	-0.007	0.011	0.559
CCND1	221	0.005	0.001	<0.001	1.005(1.002~1.007)	0.000	0.000	0.817
TP53	302	0.002	0.001	0.018	1.002(1.000~1.004)	0.000	0.000	0.387
INS	456	0.004	0.001	<0.001	1.004(1.002~1.006)	0.000	0.000	0.136

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