Journal of Shandong University (Health Sciences) ›› 2025, Vol. 63 ›› Issue (12): 6-16.doi: 10.6040/j.issn.1671-7554.0.2025.0386

• Clinical Medicine • Previous Articles    

Causal association between 20 amino acids and coronary heart disease: a Mendelian randomization study

YANG Huimin1,2, GONG Wanli1,2, HOU Yaqi1,2, WU Jing2,3, WANG Yang1,2, HE Peifeng2, YU Qi1,2   

  1. 1. School of Management, Shanxi Medical University, Jinzhong 030600, Shanxi, China;
    2. Shanxi Key Laboratory of Big Data for Clinical Decision Research, Taiyuan 030001, Shanxi, China;
    3. Academy of Medical Sciences, Shanxi Medical University, Jinzhong 030600, Shanxi, China
  • Published:2025-12-19

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Abstract: Objective To evaluate the causal relationship between genetically predicted amino acid levels and coronary heart disease(CHD)using Mendelian randomization(MR)methods. Methods We used publicly available datasets from OpenGWAS and FinnGen databases to investigate genome-wide association results between 20 amino acids and CHD from a genetic perspective. Bayesian weighted Mendelian randomization(BWMR)was employed to verify the associations, while reverse MR was used to assess potential reverse causality. Subsequently, sensitivity analyses were performed to limit the effects of heterogeneity and horizontal pleiotropy. Finally, multivariate Mendelian randomization(MVMR)was applied to determine the independent regulatory effects of amino acids on CHD. Results Inverse variance weighted analysis indicated that alanine(OR=1.151, 95%CI: 1.029-1.288, P=0.014)and glutamine(OR=1.087, 95%CI: 1.002-1.179, P=0.044)positively regulate the development of CHD, while higher levels of glycine(OR=0.921, 95%CI: 0.881-0.963, P<0.001)were associated with lower CHD risk, the overall significance level was controlled at 0.05 using the Bonferroni correction. BWMR strengthened the reliability of these causal associations. Cochrans Q test, MR-Egger intercept test, and MR-PRESSO global test demonstrated the robustness of the results(P<0.05). In the reverse MR analysis, CHD risk was positively correlated with tyrosine levels(OR=1.029, 95%CI: 1.007-1.052, P=0.010). MVMR suggested an independent regulatory effect of glycine on CHD(OR=0.879, 95%CI: 0.775-0.997, P=0.004). The promoting effects of alanine and glutamine on CHD may be influenced by factors such as diabetes, triglycerides, C-reactive protein, and hypertension. Conclusion This study demonstrates a significant causal relationship between alanine, glutamine, glycine, and CHD. Additionally, it reveals that genetically predicted higher CHD risk is associated with tyrosine levels.

Key words: Coronary heart disease, Amino acids, Mendelian randomization, Causality, MVMR analysis

CLC Number: 

  • R514.4
[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 Bonferronis 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
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