山东大学学报 (医学版) ›› 2025, Vol. 63 ›› Issue (12): 6-16.doi: 10.6040/j.issn.1671-7554.0.2025.0386
• 临床医学 • 上一篇
杨慧敏1,2,龚万里1,2,侯雅琪1,2,吴静2,3,王洋1,2,贺培凤2,于琦1,2
YANG Huimin1,2, GONG Wanli1,2, HOU Yaqi1,2, WU Jing2,3, WANG Yang1,2, HE Peifeng2, YU Qi1,2
摘要: 目的 利用孟德尔随机化(Mendelian randomization, MR)方法评估遗传预测的氨基酸水平与冠心病(coronary heart disease, CHD)之间的因果关系。 方法 基于OpenGWAS和FinnGen数据库的公开数据集,从遗传学角度探讨20种氨基酸与CHD的全基因组关联结果。同时利用贝叶斯加权孟德尔随机化(Bayesian weighted Mendelian randomization, BWMR)方法验证相关性,反向MR评估逆向关系。随后,进行敏感性分析减弱异质性和水平多效性的影响。最后,通过多变量孟德尔随机化(multivariate Mendelian randomization, MVMR)方法确定氨基酸对CHD的独立调节作用。 结果 逆方差加权法表明,丙氨酸(OR=1.151,95%CI:1.029~1.288,P=0.014)和谷氨酰胺(OR=1.087,95%CI:1.002~1.179,P=0.044)正向调节CHD的发生发展,而较高甘氨酸的水平(OR:0.921,95%CI:0.881~0.963,P<0.001)与较低CHD风险相关,通过 Bonferroni 校正将整体显著性水平控制在0.05以内。BWMR强化因果关联的可靠性,Cochrans Q检验、MR-Egger截距检验和MR-PRESSO全局检验证明结果稳健(P<0.05)。在反向MR分析中,CHD风险与酪氨酸(OR=1.029,95%CI:1.007~1.052,P=0.010)水平呈正相关。MVMR提示甘氨酸(OR=0.879,95%CI:0.775~0.997,P=0.004)对CHD的独立调节作用。而丙氨酸和谷氨酰胺对CHD的促进作用可能受糖尿病、甘油三酯、C反应蛋白和高血压等因素影响。 结论 丙氨酸、谷氨酰胺和甘氨酸与CHD存在显著的因果关系。同时,揭示遗传预测的较高CHD风险与酪氨酸水平相关。
中图分类号:
| [1] Savira F, Wang BH, Kompa AR, et al. The impact of coronary heart disease prevention on work productivity: a 10-year analysis[J]. Eur J Prev Cardiol, 2021, 28(4): 418-425. [2] 朱赟, 魏佳明, 林瑞芳, 等. 免疫细胞与冠心病风险: 基于血清代谢物介导的孟德尔随机化研究[J]. 中国循环杂志, 2025, 40(5): 508-515. ZHU Yun, WEI Jiaming, LIN Ruifang, et al. Immune cells and the risk of coronary heart disease: a Mendelian randomization study mediated by serum metabolites[J]. Chinese Circulation Journal, 2025, 40(5): 508-515. [3] Mensah GA, Fuster V, Roth GA. A heart-healthy and stroke-free world: using data to inform global action[J]. J Am Coll Cardiol, 2023, 82(25): 2343-2349. [4] 刘明波, 何新叶, 杨晓红, 等. 《中国心血管健康与疾病报告2023》要点解读[J]. 中国心血管杂志, 2024, 29(4): 305-324. LIU Mingbo, HE Xinye, YANG Xiaohong, et al. Interpretation of Report on Cardiovascular Health and Diseases in China 2023[J]. Chinese Journal of Cardiovascular Medicine, 2024, 29(4): 305-324. [5] Malakar AK, Choudhury D, Halder B, et al. A review on coronary artery disease, its risk factors, and therapeutics[J]. J Cell Physiol, 2019, 234(10): 16812-16823. [6] Djoussé L, Zhou GH, McClelland RL, et al. Egg consumption, overall diet quality, and risk of type 2 diabetes and coronary heart disease: a pooling project of US prospective cohorts[J]. Clin Nutr, 2021, 40(5): 2475-2482. [7] Katta N, Loethen T, Lavie CJ, et al. Obesity and coronary heart disease: epidemiology, pathology, and coronary artery imaging[J]. Curr Probl Cardiol, 2021, 46(3): 100655. doi: 10.1016/j.cpcardiol.2020.100655 [8] Li HY, Sun K, Zhao RP, et al. Inflammatory biomarkers of coronary heart disease[J]. Front Biosci(Schol Ed), 2018, 10(1): 185-196. [9] Volpe M, Gallo G. Hypertension, coronary artery disease and myocardial ischemic syndromes[J]. Vascul Pharmacol, 2023, 153: 107230. doi: 10.1016/j.vph.2023.107230 [10] Wang B, Mo X, Wu Z, Guan X. Systematic review and meta-analysis of the correlation between plasma homocysteine levels and coronary heart disease[J]. J Thorac Dis, 2022, 14(3): 646-653. [11] Zhao LL, Qiu XJ, Wang WB, et al. NMR metabolomics and random forests models to identify potential plasma biomarkers of blood stasis syndrome with coronary heart disease patients[J]. Front Physiol, 2019, 10: 1109. doi: 10.3389/fphys.2019.01109 [12] Kim K, Kim DS, Kim KN. Serum alanine aminotransferase level as a risk factor for coronary heart disease prediction in Koreans: analysis of the Korea national health and nutrition examination survey(V-1, 2010 and V-2, 2011)[J]. Korean J Fam Med, 2019, 40(2): 124-128. [13] Bhandage AK, Barragan A. GABAergic signaling by cells of the immune system: more the rule than the exception[J]. Cell Mol Life Sci, 2021, 78(15): 5667-5679. [14] 郭佩佩, 徐洋, 石嘉琪, 等. 氨基酸代谢在自身免疫性肝炎中的作用机制及相关治疗靶点[J]. 临床肝胆病杂志, 2025, 41(3): 547-551. GUO Peipei, XU Yang, SHI Jiaqi, et al. Role of amino acid metabolism in autoimmune hepatitis and related therapeutic targets[J]. Journal of Clinical Hepatology, 2025, 41(3): 547-551. [15] Chen JN, Zhang SL, Wu JX, et al. Essential role of nonessential amino acid glutamine in atherosclerotic cardiovascular disease[J]. DNA Cell Biol, 2020, 39(1): 8-15. [16] Ling ZN, Jiang YF, Ru JN, et al. Amino acid metabolism in health and disease[J]. Signal Transduct Target Ther, 2023, 8(1): 345. doi: 10.1038/s41392-023-01569-3 [17] Rom O, Liu YH, Finney AC, et al. Induction of glutathione biosynthesis by glycine-based treatment mitigates atherosclerosis[J]. Redox Biol, 2022, 52: 102313. doi: 10.1016/j.redox.2022.102313 [18] Dziedzic M, Józefczuk E, Guzik TJ, et al. Interplay between plasma glycine and branched-chain amino acids contributes to the development of hypertension and coronary heart disease[J]. Hypertension, 2024, 81(6): 1320-1331. [19] 黄馨, 王梦雪, 付书璠, 等. 代谢综合征及其组分与消化系统恶性肿瘤的因果关联: 两样本孟德尔随机化研究[J]. 山东大学学报(医学版), 2025, 63(5): 86-94. HUANG Xin, WANG Mengxue, FU Shufan, et al. Causal association of metabolic syndrome and its components with digestive system malignancies: a two-sample Mendelian randomized study[J]. Journal of Shandong University(Health Sciences), 2025, 63(5): 86-94. [20] 张天鑫, 张婷, 黄鑫, 等. 氨基酸与2型糖尿病因果关系的孟德尔随机化分析[J]. 山东大学学报(医学版), 2023, 61(5): 102-107. ZHANG Tianxin, ZHANG Ting, HUANG Xin, et al. A Mendelian randomization analysis on the causal associations between amino acids and type 2 diabetes[J]. Journal of Shandong University(Health Sciences), 2023, 61(5): 102-107. [21] Valencia-Hernández CA, Fabiola Greco M, Sundaram V, et al. Asthma and incident coronary heart disease: an observational and Mendelian randomisation study[J]. Eur Respir J, 2023, 62(5): 2301788. doi: 10.1183/13993003.01788-2023 [22] Gan T, Hu J, Liu WH, et al. Causal association between Anemia and cardiovascular disease: a 2-sample bidirectional Mendelian randomization study[J]. J Am Heart Assoc, 2023, 12(12): e029689. doi: 10.1161/JAHA.123.029689 [23] Luo J, le Cessie S, van Heemst D, et al. Diet-derived circulating antioxidants and risk of coronary heart di-sease: a Mendelian randomization study[J]. J Am Coll Cardiol, 2021, 77(1): 45-54. [24] Sanderson E. Multivariable Mendelian randomization and mediation[J]. Cold Spring Harb Perspect Med, 2021, 11(2): a038984. doi: 10.1101/cshperspect.a038984 [25] Skrivankova VW, Richmond RC, Woolf BAR, et al. Strengthening the reporting of observational studies in epidemiology using Mendelian randomization: the STROBE-MR statement[J]. JAMA, 2021, 326(16): 1614-1621. [26] Shin SY, Fauman EB, Petersen AK, et al. An atlas of genetic influences on human blood metabolites[J]. Nat Genet, 2014, 46(6): 543-550 [27] Kurki MI, Karjalainen J, Palta P, et al. FinnGen provides genetic insights from a well-phenotyped isolated population[J]. Nature, 2023, 613(7944): 508-518. [28] Kwok MK, Schooling CM. Herpes simplex virus and Alzheimer’s disease: a Mendelian randomization study[J]. Neurobiol Aging, 2021, 99: 101. doi: 10.1016/j.neurobiolaging.2020.09.025 [29] Gong WL, Zhou JY, Hou YQ, et al. The causal relationship between immune cells mediating FIT3L, CCL4, OSM, and skin-derived deteriorated tumors[J]. Skin Res Technol, 2024, 30(7): e13774. doi: 10.1111/srt.13774 [30] 李建锋, 张展, 丁新华, 等. 欧洲人群饮食因素与认知功能障碍关系的孟德尔随机化分析[J]. 山东大学学报(医学版), 2025, 63(4): 36-43. LI Jianfeng, ZHANG Zhan, DING Xinhua, et al. Mendelian randomization analysis of dietary factors and cognitive impairment in European populations[J]. Journal of Shandong University(Health Sciences), 2025, 63(4): 36-43. [31] Burgess S, Butterworth A, Thompson SG. Mendelian randomization analysis with multiple genetic variants using summarized data[J]. Genet Epidemiol, 2013, 37(7): 658-665. [32] Hu S, Lin ZN, Hu MJ, et al. Causal relationships of circulating amino acids with cardiovascular disease: a trans-ancestry Mendelian randomization analysis[J]. J Transl Med, 2023, 21(1): 699. doi: 10.1186/s12967-023-04580-y [33] Burgess S, Thompson SG. Interpreting findings from Mendelian randomization using the MR-Egger method[J]. Eur J Epidemiol, 2017, 32(5): 377-389. [34] Zhao J, Ming JS, Hu XH, et al. Bayesian weighted Mendelian randomization for causal inference based on summary statistics[J]. Bioinformatics, 2020, 36(5): 1501-1508. [35] Sedgwick P. Multiple hypothesis testing and Bonferronis correction[J]. BMJ, 2014, 349: g6284. doi: 10.1136/bmj.g6284 [36] Li RT, He H, Fang SH, et al. Time series characteristics of serum branched-chain amino acids for early diagnosis of chronic heart failure[J]. J Proteome Res, 2019, 18(5): 2121-2128. [37] Boirie Y, Pinel A, Guillet C. Protein and amino acids in obesity: friends or foes?[J]. Curr Opin Clin Nutr Metab Care, 2023, 26(6): 508-513. [38] Sun W, Zhao EH, Cui HJ. Target enzymes in serine-glycine-one-carbon metabolic pathway for cancer therapy[J]. Int J Cancer, 2023, 152(12): 2446-2463. [39] Ji Y, Fan XX, Zhang YC, et al. Glycine regulates mucosal immunity and the intestinal microbial composition in weaned piglets[J]. Amino Acids, 2022, 54(3): 385-398. [40] Alves A, Bassot A, Bulteau AL, et al. Glycine metabolism and its alterations in obesity and metabolic diseases[J]. Nutrients, 2019, 11(6): 1356. doi: 10.3390/nu11061356 [41] Simmons RM, McKnight SM, Edwards AK, et al. Obesity increases hepatic glycine dehydrogenase and aminomethyltransferase expression while dietary Glycine supplementation reduces white adipose tissue in Zucker diabetic fatty rats[J]. Amino Acids, 2020, 52(10): 1413-1423. [42] Kumar P, Liu C, Hsu JW, et al. Glycine and N-acetylcysteine(GlyNAC)supplementation in older adults improves glutathione deficiency, oxidative stress, mitochondrial dysfunction, inflammation, insulin resistance, endothelial dysfunction, genotoxicity, muscle strength, and cognition: results of a pilot clinical trial[J]. Clin Transl Med, 2021, 11(3): e372. doi: 10.1002/ctm2.372 [43] Guasch-Ferré M, Santos JL, Martínez-González MA, et al. Glycolysis/gluconeogenesis- and tricarboxylic acid cycle-related metabolites, Mediterranean diet, and type 2 diabetes[J]. Am J Clin Nutr, 2020, 111(4): 835-844. [44] Wang TJ, Larson MG, Vasan RS, et al. Metabolite profiles and the risk of developing diabetes[J]. Nat Med, 2011, 17(4): 448-453. [45] 王子贤, 赖伟华, 钟诗龙. 两样本孟德尔随机化方法分析血液代谢物与冠心病的因果关系[J]. 南方医科大学学报, 2021, 41(2): 272-278. WANG Zixian, LAI Weihua, ZHONG Shilong. Investigating the causal relationship between human blood metabolites and coronary artery disease using two-sample Mendelian randomization[J]. Journal of Southern Medical University, 2021, 41(2): 272-278. [46] Kazumi T, Kawaguchi A, Hirano T, et al. Serum alanine aminotransferase is associated with serum adiponectin, C-reactive protein and apolipoprotein B in young healthy men[J]. Horm Metab Res, 2006, 38(2): 119-124. [47] Mao JY, Yan YH, Li HL, et al. Glutamine deficiency links clindamycin-induced dysbiosis and intestinal barrier dysfunction in mice[J]. Br J Nutr, 2021, 126(3): 366-374. [48] Grosheva I, Zheng DP, Levy M, et al. High-throughput screen identifies host and microbiota regulators of intestinal barrier function[J]. Gastroenterology, 2020, 159(5): 1807-1823. [49] Sookoian S, Pirola CJ. Alanine and aspartate aminotransferase and glutamine-cycling pathway: their roles in pathogenesis of metabolic syndrome[J]. World J Gastroenterol, 2012, 18(29): 3775-3781. [50] Wang XY, Yang RY, Zhang WD, et al. Serum glutamate and glutamine-to-glutamate ratio are associated with coronary angiography defined coronary artery disease[J]. Nutr Metab Cardiovasc Dis, 2022, 32(1): 186-194. [51] Murcy F, Borowczyk C, Gourion-Arsiquaud S, et al. GLS2 links glutamine metabolism and atherosclerosis by remodeling artery walls[J]. Nat Cardiovasc Res, 2024, 3(12): 1454-1467. [52] 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. doi: 10.1038/ncomms11122 [53] Chu C, Liu SQ, Nie LG, et al. The interactions and biological pathways among metabolomics products of patients with coronary heart disease[J]. Biomed Pharmacother, 2024, 173: 116305. doi: 10.1016/j.biopha.2024.116305 [54] Obeid OA. Plasma amino acid concentrations in patients with coronary heart disease: a comparison between U.K. Indian Asian and Caucasian men[J]. Int J Vitam Nutr Res, 2005, 75(4): 267-273. [55] Dehghanbanadaki H, Dodangeh S, Parhizkar Roudsari P, et al. Metabolomics profile and 10-year atherosclerotic cardiovascular disease(ASCVD)risk score[J]. Front Cardiovasc Med, 2023, 10: 1161761. doi: 10.3389/fcvm.2023.1161761 [56] Hu J, Yao J, Deng SL, et al. Differences in metabolomic profiles between black and white women and risk of coronary heart disease: an observational study of women from four US cohorts[J]. Circ Res, 2022, 131(7): 601-615. [57] Lu J, Hu HC, Xiu JM, et al. Machine learning-driven risk assessment of coronary heart disease: analysis of NHANES data from 1999 to 2018[J]. Zhong Nan Da Xue Xue Bao Yi Xue Ban, 2024, 49(8): 1175-1186. [58] Zhang ZX, Wang L, Zhan Y, et al. Clinical value and expression of Homer 1, homocysteine, S-adenosyl-l-homocysteine, fibroblast growth factors 23 in coronary heart disease[J]. BMC Cardiovasc Disord, 2022, 22(1): 215. doi: 10.1186/s12872-022-02554-4 [59] Huang YF, Hui Q, Gwinn M, et al. Sexual differences in genetic predisposition of coronary artery disease[J]. Circ Genom Precis Med, 2021, 14(1): e003147. doi: 10.1161/CIRCGEN.120.003147 [60] Silander K, Alanne M, Kristiansson K, et al. Gender differences in genetic risk profiles for cardiovascular disease[J]. PLoS One, 2008, 3(10): e3615. doi: 10.1371/journal.pone.0003615 |
| [1] | 王乐,罗清馨,吴思佳,吴雨桐,葛祎蕾,俞一凡,韦云,吉寒冰,刘铁梅,张紫妍,修佳伟,薛付忠,李洪凯. 虚弱和癫痫关联研究:前瞻性队列和孟德尔随机化分析[J]. 山东大学学报 (医学版), 2025, 63(9): 20-30. |
| [2] | 刘位龙,王玎,赵超,王宁,张旭,苏萍,宋书典,张娜,迟蔚蔚. 基于BERT和图注意力网络的医疗文本因果关系抽取算法[J]. 山东大学学报 (医学版), 2025, 63(8): 61-68. |
| [3] | 王雪梅,杨豪,宋洋,程世超,张婷婷,王艳春. 抗糖尿病药物与女性恶性肿瘤的因果关联:一项两样本孟德尔随机化分析[J]. 山东大学学报 (医学版), 2025, 63(6): 67-77. |
| [4] | 陈绪军,申林,陈军,于涛,曹广庆,肖飞. 解剖完全再血管化是冠心病外科治疗的新策略[J]. 山东大学学报 (医学版), 2025, 63(5): 12-17. |
| [5] | 黄馨,王梦雪,付书璠,张琦悦,徐力. 代谢综合征及其组分与消化系统恶性肿瘤的因果关联:两样本孟德尔随机化研究[J]. 山东大学学报 (医学版), 2025, 63(5): 86-94. |
| [6] | 国科,陈绪军,郑宝石,黄克力,王晓武,陈景伟,林宇,罗俊辉,王海晨,王振东,廖成全,李有金,陈文生. 解剖完全再血管化全动脉冠脉旁路移植术多中心应用中期结果[J]. 山东大学学报 (医学版), 2025, 63(5): 18-25. |
| [7] | 王小磊,方骏,王安,朱武晖,史光军. 两样本孟德尔随机化分析肠道菌群与肝外胆管癌的因果关系[J]. 山东大学学报 (医学版), 2025, 63(4): 44-50. |
| [8] | 李建锋,张展,丁新华,高奋堂,何勤利,谢萍. 欧洲人群饮食因素与认知功能障碍关系的孟德尔随机化分析[J]. 山东大学学报 (医学版), 2025, 63(4): 36-43. |
| [9] | 杨慧,苏士晶,李芬. 基于双向孟德尔随机化法探讨组织蛋白酶与衰弱的因果关联[J]. 山东大学学报 (医学版), 2025, 63(2): 67-76. |
| [10] | 常宇,胡云峰,王会丰,郭静,张跳,郝雅琴,刘雨. 阑尾切除术与结直肠癌发病风险关联的孟德尔随机化研究[J]. 山东大学学报 (医学版), 2025, 63(2): 77-83. |
| [11] | 杨春桃,左玉. MMP1、MMP9基因与慢性牙周炎的因果关系:基于两样本孟德尔随机化研究[J]. 山东大学学报 (医学版), 2025, 63(11): 87-97. |
| [12] | 周坤,刘婷,姜艳菊,胡泽楷,李宇佳,冯武仪,黄继莉,叶汪泉,赵小峰,胡军. 孟德尔随机化分析膝骨关节炎疼痛与肌力的因果关联[J]. 山东大学学报 (医学版), 2025, 63(11): 61-67. |
| [13] | 袁宗怀,潘广晔,迟曰梅,安传国,张永刚. 孟德尔随机化分析低级别浆液性卵巢癌与乳腺癌的因果关系[J]. 山东大学学报 (医学版), 2025, 63(1): 99-107. |
| [14] | 张展,李建锋,李燕玲,王博雯,昂文成林龙珠,王鑫,张小明,谢萍. 饮食因素与子痫前期因果关系的孟德尔随机化分析[J]. 山东大学学报 (医学版), 2024, 62(8): 59-66. |
| [15] | 冯悦,俞一凡,吴思佳,李洪凯,薛付忠. 内脏脂肪组织与肺部疾病的孟德尔随机化研究[J]. 山东大学学报 (医学版), 2024, 62(7): 48-55. |
|
||