上海交通大学学报（医学版）

上海交通大学学报（医学版） >

2026 , Vol. 46 >Issue 3: 340 - 347

DOI: https://doi.org/10.3969/j.issn.1674-8115.2026.03.008

论著 · 循证医学

基于两样本孟德尔随机化分析脂质体与原发性高血压的因果关系

  • 黄玺 ,
  • 侯钦午 ,
  • 张兆伟 ,
  • 王亚南 ,
  • 杨庆辉 ,
  • 程玲
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  • 1.上海市浦东新区北蔡社区卫生服务中心全科，上海 201204
    2.同济大学附属东方医院心血管内科，上海 200120
    3.同济大学附属东方医院中医针灸科，上海 200120
杨庆辉，主任医师，博士；电子信箱：qinghuiyang@tongji.edu.cn。

收稿日期: 2025-09-12

  录用日期: 2025-12-05

  网络出版日期: 2026-03-30

基金资助

上海市浦东新区科技发展基金事业单位民生科研专项医疗卫生项目(PKJ2024-Y64);上海市浦东新区卫生健康委员会项目(PWZzk2022-25);上海市浦东新区卫生健康委员会项目(YC-2023-0612,PWYq2025-01)

收起

Causal relationship between liposome and essential hypertension based on two-sample Mendelian randomization analysis

  • Huang Xi ,
  • Hou Qinwu ,
  • Zhang Zhaowei ,
  • Wang Yanan ,
  • Yang Qinghui ,
  • Cheng Ling
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  • 1.General Practice Department, Beicai Community Health Service Center, Pudong New Area, Shanghai 201204, China
    2.Department of Cardiology, East Hospital, Tongji University, Shanghai 200120, China
    3.Department of Traditional Chinese Medicine Acupuncture and Moxibustion, East Hospital, Tongji University, Shanghai 200120, China
Yang Qinghui, E-mail: qinghuiyang@tongji.edu.cn.

Received date: 2025-09-12

  Accepted date: 2025-12-05

  Online published: 2026-03-30

Supported by

Medical and Health Project of the Special Fund for People′s Livelihood Scientific Research in Public Institutions under the Science and Technology Development Fund of Pudong New Area, Shanghai(PKJ2024-Y64);Project of the Health Commission of Pudong New Area, Shanghai(PWZzk2022-25)

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摘要

目的·采用两样本孟德尔随机化（two-sample Mendelian randomization，TSMR）方法分析脂质体与原发性高血压的因果关系。方法·原发性高血压的全基因组关联分析（genome-wide association study，GWAS）数据来自FinnGen数据库，脂质体数据来自欧洲生物信息学研究所（European Bioinformatics Institute，EBI）。从EBI的GWAS数据库下载179种脂质体数据，并筛选相关的单核苷酸多态性（single-nucleotide polymorphism，SNP）作为工具变量。采用逆方差加权法（inverse-variance weighted，IVW）、MR-Egger回归、加权中位数法、加权模式法和简单模式法结合敏感性分析，综合评估179种脂质体与原发性高血压之间的因果关联。结果·共筛选出8种与原发性高血压相关的脂质体。IVW显示，6种脂质体增加原发性高血压风险，分别为甘油三酯（52∶3）（OR=1.061，95%CI 1.022~1.101，P=0.002），磷脂酰肌醇（16∶0-18∶1）（OR=1.066，95%CI 1.025~1.107，P=0.001），甘油三酯（50∶2）（OR=1.086，95%CI 1.036~1.139，P<0.001），甘油三酯（54∶3）（OR=1.062，95%CI 1.027~1.099，P<0.001），甘油三酯（50∶1）（OR=1.098，95%CI 1.045~1.154，P<0.001）和甘油三酯（52∶2）（OR=1.071，95%CI 1.035~1.110，P<0.001）。2种脂质体减少原发性高血压风险，分别为鞘磷脂（d40∶2）（OR=0.968，95%CI 0.937~0.999，P=0.042）和磷脂酰胆碱（O-16∶1-18∶1）（OR=0.960，95%CI 0.924~0.998，P=0.038）。其他4种方法显示的因果方向与IVW一致。Cochran′s Q检验显示存在轻微异质性，但对整体结果的稳健性影响有限。MR-Egger回归表明不存在水平多效性。留一法检验表明结果具有较高的稳健性。反向MR分析显示，原发性高血压发病不改变上述脂质体的类型。结论·特定脂质体与原发性高血压存在因果关联。甘油三酯（52∶3、50∶2、54∶3、50∶1、52∶2）和磷脂酰肌醇（16∶0-18∶1）是原发性高血压的危险因素，它们可能通过代谢紊乱促进原发性高血压发生。而鞘磷脂（d40∶2）和磷脂酰胆碱（O-16∶1-18∶1）或对原发性高血压的发生具有保护作用。

关键词： 脂质体; 原发性高血压; 孟德尔随机化; 因果关系

本文引用格式

黄玺 , 侯钦午 , 张兆伟 , 王亚南 , 杨庆辉 , 程玲 . 基于两样本孟德尔随机化分析脂质体与原发性高血压的因果关系[J]. 上海交通大学学报（医学版）, 2026 , 46(3) : 340 -347 . DOI: 10.3969/j.issn.1674-8115.2026.03.008

Abstract

Objective ·A two-sample Mendelian randomization (TSMR) approach was employed to investigate the causal relationship between liposomes and essential hypertension. Methods ·Genome-wide association study (GWAS) data for essential hypertension were obtained from the FinnGen database, while lipid profile data were sourced from the European Bioinformatics Institute (EBI). Data on 179 liposomes were downloaded from the EBI GWAS database, and relevant single-nucleotide polymorphisms (SNPs) were screened as instrumental variables. Inverse-variance weighted (IVW), MR-Egger, weighted median, weighted mode, and simple mode methods, combined with sensitivity analysis, were employed to evaluate the causal associations between the 179 liposomes and essential hypertension. Results ·Eight types of liposomes were identified as being associated with essential hypertension. According to the IVW results, six types of liposomes significantly increased the risk of essential hypertension, including triglyceride (52:3) (OR=1.061, 95%CI 1.022‒1.101, P=0.002), phosphatidylinositol (16:0‒18:1) (OR=1.066, 95%CI 1.025‒1.107, P=0.001), triglyceride (50:2) (OR=1.086, 95%CI 1.036‒1.139, P<0.001), triglyceride (54:3) (OR=1.062, 95%CI 1.027‒1.099, P<0.001), triglyceride (50:1) (OR=1.098, 95%CI 1.045‒1.154, P<0.001), and triglyceride (52:2) (OR=1.071, 95%CI 1.035‒1.110, P<0.001). Two types of liposome reduced the risk of essential hypertension, including sphingomyelin (d40:2) (OR=0.968, 95%CI 0.937‒0.999, P=0.042) and phosphatidylcholine (O-16:1‒18:1) (OR=0.960, 95%CI 0.924‒0.998, P=0.038). The causal directions revealed by the other four methods were consistent with those of the IVW method. Cochran′s Q test revealed slight heterogeneity, but its impact on the robustness of the overall results was limited. MR-Egger regression indicated no evidence of horizontal pleiotropy. Leave-one-out cross-validation demonstrated high robustness of the results. Reverse MR analysis indicated that the onset of essential hypertension did not alter the type of the aforementioned liposomes. Conclusion ·There is a causal relationship between specific liposomes and essential hypertension. Triglycerides (52:3, 50:2, 54:3, 50:1, 52:2) and phosphatidylinositol (16:0‒18:1) are risk factors for essential hypertension, which may promote hypertension development through metabolic disturbances. Moreover, sphingomyelin (D40:2) and phosphatidylcholine (O-16:1‒18:1) may have protective effects against the occurrence of essential hypertension.

Key words： liposome; essential hypertension; Mendelian randomization (MR); causal relationship

参考文献

[1] Burnier M, Damianaki A. Hypertension as cardiovascular risk factor in chronic kidney disease[J]. Circ Res. 2023, 132(8): 1050-1063.
[2] Tiwari S, Riazi S, Ecelbarger C A. Insulin′s impact on renal sodium transport and blood pressure in health, obesity, and diabetes[J]. Am J Physiol Renal Physiol, 2007, 293(4): F974-F984.
[3] Vasan R S, Beiser A, Seshadri S, et al. Residual lifetime risk for developing hypertension in middle-aged women and men: the Framingham Heart Study[J]. JAMA, 2002, 287(8): 1003-1010.
[4] Lloyd-Jones D M, Evans J C, Levy D. Hypertension in adults across the age spectrum: current outcomes and control in the community[J]. JAMA, 2005, 294(4): 466-472.
[5] Cao X, Wang X, Tian Y X, et al. Trends and sociodemographic patterns in hypertension prevalence and treatment in China[J]. Med, 2025, 6(11): 100808.
[6] 中国高血压防治指南修订委员会, 高血压联盟(中国), 中国医疗保健国际交流促进会高血压分会, 等. 中国高血压防治指南(2024年修订版)[J]. 中华高血压杂志(中英文), 2024, 32(7): 603-700.
  Revision Committee of Chinese Guidelines for the Management of Hypertension, Hypertension League (China), Hypertension Branch of China International Exchange and Promotive Association for Medical and Health Care, et al. Chinese guidelines for the management of hypertension (2024 revised edition)[J]. Chinese Journal of Hypertension, 2024, 32(7): 603-700.
[7] Liu W F, Yang C Z, Lei F, et al. Major lipids and lipoprotein levels and risk of blood pressure elevation: a Mendelian randomisation study[J]. EBioMedicine, 2024, 100: 104964.
[8] Bangham A D, Standish M M, Watkins J C. Diffusion of univalent ions across the lamellae of swollen phospholipids[J]. J Mol Biol, 1965, 13(1): 238-252.
[9] 蔡晓璇, 吕应年, 戚怡. 长循环脂质体的应用领域和作用机制[J]. 中国组织工程研究, 2022, 26(16): 2613-2617.
  Cai X X, Lü Y N, Qi Y. Long-circulating liposomes: application and mechanism[J]. Chinese Journal of Tissue Engineering Research, 2022, 26(16): 2613-2617.
[10] 刘彦彬, 黄蕾, 张英杰, 等. 氯膦酸二钠脂质体改善高血压小鼠血管内皮细胞功能及心肌肥厚[J]. 中国动脉硬化杂志, 2017, 25(4): 325-331.
  Liu Y B, Huang L, Zhang Y J, et al. Clodronate liposome ameliorated endothelial function and cardiac hypertrophy in angiotensin Ⅱ hypertensive mice[J]. Chinese Journal of Arteriosclerosis, 2017, 25(4): 325-331.
[11] 陆苑, 陆玉婷, 杨思敏, 等. 金钱菇中降血压肽的纯化和磁性脂质体分离鉴定[J]. 广西科技大学学报, 2023, 34(3): 116-122, 138.
  Lu Y, Lu Y T, Yang S M, et al. Purification of anti-hypertensive peptide and separation identification of magnetic liposome from Lentinus edodes[J]. Journal of Guangxi University of Science and Technology, 2023, 34(3): 116-122, 138.
[12] 郭婧仪. 超声联合阳离子脂质微泡介导siRNA-Cyp11b2抑制醛固酮合成酶的研究[D]. 成都: 成都医学院, 2024.
  Guo J Y. Ultrasound combined with cationic lipid microbubbles mediates the inhibition of aldosterone synthase by siRNA-Cyp11b2[D]. Chengdu:Chengdu Medical College, 2024.
[13] 王金鑫. 金枪鱼ACE抑制肽的筛选鉴定及其脂质体的构建[D]. 烟台: 烟台大学, 2024.
  Wang J X. Screening and identification of ACE inhibiting peptides from tuna and construction of liposomes[D]. Yantai: Yantai University, 2024.
[14] Lawlor D A, Harbord R M, Sterne J A C, et al. Mendelian randomization: using genes as instruments for making causal inferences in epidemiology[J]. Stat Med, 2008, 27(8): 1133-1163.
[15] Orrù V, Steri M, Sidore C, et al. Complex genetic signatures in immune cells underlie autoimmunity and inform therapy[J]. Nat Genet, 2020, 52(10): 1036-1045.
[16] Ottensmann L, Tabassum R, Ruotsalainen S E, et al. Genome-wide association analysis of plasma lipidome identifies 495 genetic associations[J]. Nat Commun, 2023, 14(1): 6934.
[17] Gagliano Taliun S A, Evans D M. Ten simple rules for conducting a Mendelian randomization study[J]. PLoS Comput Biol, 2021, 17(8): e1009238.
[18] Skrivankova V W, Richmond R C, Woolf B A R, et al. Strengthening the reporting of observational studies in epidemiology using Mendelian randomization: the STROBE-MR statement[J]. JAMA, 2021, 326(16): 1614-1621.
[19] Burgess S, Thompson S G. Interpreting findings from Mendelian randomization using the MR-Egger method[J]. Eur J Epidemiol, 2017, 32(5): 377-389.
[20] Kettunen J, Demirkan A, Würtz P, et al. Genome-wide study for circulating metabolites identifies 62 loci and reveals novel systemic effects of LPA[J]. Nat Commun, 2016, 7: 11122.
[21] Bowden J, Davey Smith G, Haycock P C, et al. Consistent estimation in Mendelian randomization with some invalid instruments using a weighted Median estimator[J]. Genet Epidemiol, 2016, 40(4): 304-314.
[22] Bowden J, Davey Smith G, Burgess S. Mendelian randomization with invalid instruments: effect estimation and bias detection through Egger regression[J]. Int J Epidemiol, 2015, 44(2): 512-525.
[23] 王若楠, 张德生, 白朝, 等. 甘油三酯、空腹血糖及甘油三酯葡萄糖乘积指数与高血压发病风险的前瞻性队列研究[J]. 中华流行病学杂志, 2021, 42(3): 482-487.
  Wang R N, Zhang D S, Bai Z, et al. Prospective cohort study of relationship of triglyceride, fasting blood-glucose and triglyceride glucose product index with risk of hypertension[J]. Chinese Journal of Epidemiology, 2021, 42(3): 482-487.
[24] 顾亦斌, 顾淑君, 张秋伊, 等. 2021—2023年江苏省35~75岁居民高甘油三酯血症与高血压患病的关系[J]. 卫生研究, 2025, 54(5): 770-775, 783.
  Gu Y B, Gu S J, Zhang Q Y, et al. Relationship between hypertriglyceridemia and hypertension among adults aged 35?75 years in Jiangsu Province from 2021 to 2023[J]. Journal of Hygiene Research, 2025, 54(5): 770-775, 783.
[25] 苏工. 苯扎贝特对高血压合并高甘油三酯血症患者血压的影响及机制探讨[D]. 北京: 中国人民解放军军医进修学院, 2003.
  Su G. Effects of bezafibrate on blood pressure in hypertensive patients with hypertriglyceridemia[D]. Beijing: Chinese People′s Liberation Army Medical School, 2003.
[26] Wen Y, Chen Y Q, Konrad R J. The regulation of triacylglycerol metabolism and lipoprotein lipase activity[J]. Adv Biol, 2022, 6(10): e2200093.
[27] 王锦淳. 黄芩茎叶总黄酮对高甘油三酯血清诱导的血管内皮细胞氧化损伤的保护作用及机制研究[D]. 扬州: 扬州大学, 2011.
  Wang J C. Study the protective effect and mechanism of Scutellaria baicalensis stem-leaf total flavonoid against the vascular endothelial cells oxidative injury induced by high triglyceride blood serum[D]. Yangzhou: Yangzhou University, 2011.
[28] 蔡毕青. FAR在不同甘油三酯水平与老年冠心病患者冠脉病变严重程度的相关性研究[D]. 成都: 成都医学院, 2024.
  Cai B Q. Correlation between FAR and coronary artery lesion severity in elderly patients with coronary heart disease in different triglyceride levels[D]. Chengdu: Chengdu Medical College, 2024.
[29] Viaud J, Payrastre B. Phosphoinositides: the lipids coordinating cell dynamics[J]. Med Sci (Paris), 2015, 31(11): 996-1005.
[30] Yang J H, Saucerman J J. Phospholemman is a negative feed-forward regulator of Ca2+ in β-adrenergic signaling, accelerating β-adrenergic inotropy[J]. J Mol Cell Cardiol, 2012, 52(5): 1048-1055.
[31] Saddouk F Z, Ginnan R, Singer H A. Ca2+/calmodulin-dependent protein kinase Ⅱ in vascular smooth muscle[M]//Vascular pharmacology: smooth muscle. Amsterdam: Elsevier, 2017: 171-202.
[32] 高原. 白介素增强结合因子3调节一氧化氮产生参与高血压交感亢进的作用研究[D]. 上海: 中国人民解放军海军军医大学, 2022.
  Gao Y. Role of interleukin-enhancing binding factor 3 in regulating nitric oxide production in sympathetic hyperactivity of hypertension[D]. Shanghai: Naval Medical University of the Chinese People's Liberation Army, 2022.
[33] Zheng H, Xie X Y, Xie N Z, et al. Sphingomyelin levels in nondipper and dipper hypertensive patients[J]. Exp Ther Med, 2014, 7(3): 599-603.
[34] Borodzicz S, Czarzasta K, Kuch M, et al. Sphingolipids in cardiovascular diseases and metabolic disorders[J]. Lipids Health Dis, 2015, 14: 55.
[35] Brizuela L, Cuvillier O. Biochemical methods for quantifying sphingolipids: ceramide, sphingosine, sphingosine kinase-1 activity, and sphingosine-1-phosphate[J]. Methods Mol Biol, 2012, 874: 1-20.
[36] Gratschev D, L?f C, Heikkil? J, et al. Sphingosine kinase as a regulator of calcium entry through autocrine sphingosine 1-phosphate signaling in thyroid FRTL-5 cells[J]. Endocrinology, 2009, 150(11): 5125-5134.
[37] Fischer T H, Eiringhaus J, Dybkova N, et al. Activation of protein phosphatase 1 by a selective phosphatase disrupting peptide reduces sarcoplasmic reticulum Ca2+ leak in human heart failure[J]. Eur J Heart Fail, 2018, 20(12): 1673-1685.
[38] Arya D, Chang S H, DiMuzio P, et al. Sphingosine-1-phosphate promotes the differentiation of adipose-derived stem cells into endothelial nitric oxide synthase (eNOS) expressing endothelial-like cells[J]. J Biomed Sci, 2014, 21(1): 55.
[39] 熊雪莲. 机体代谢物与高血压病发病风险的相关性研究[D]. 十堰: 湖北医药学院, 2020.
  Xiong X L. A Study on the association of metabolites with the risk of incident hypertension[D]. Shiyan: Hubei University of Medicine, 2020.
[40] Zembowicz A, Tang J L, Wu K K. Transcriptional induction of endothelial nitric oxide synthase type Ⅲ by lysophosphatidylcholine[J]. J Biol Chem, 1995, 270(28): 17006-17010.
[41] Gong Y C, Li Q F, Ma Z T, et al. Downregulation of activating transcription factor 4 attenuates lysophosphatidycholine-induced inflammation via the NF-κB pathway[J]. Eur J Pharmacol, 2021, 911: 174457.
[42] Zheng L, McQuaw C M, Baker M J, et al. Investigating lipid-lipid and lipid-protein interactions in model membranes by ToF-SIMS[J]. Appl Surf Sci, 2008, 255(4): 1190-1192.
[43] White U A, Fitch M D, Beyl R A, et al. Racial differences in in vivo adipose lipid kinetics in humans[J]. J Lipid Res, 2018, 59(9): 1738-1744.
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