Research progress of aldehyde dehydrogenase 2 gene polymorphism in coronary heart disease

doi:10.11958/20252288

Abstract

Abstract:

Coronary heart disease (CHD) is a common clinical condition in cardiology, characterized by atherosclerotic lesions in coronary arteries leading to luminal stenosis or occlusion, which subsequently causes myocardial ischemia, hypoxia and even necrosis. Known risk factors only partially account for the pathogenesis of CHD, suggesting the involvement of other critical pathogenic mechanisms. Aldehyde dehydrogenase 2 (ALDH2), as a key mitochondrial metabolic enzyme, is widely expressed in various tissues of human body. Its activity is significantly regulated by gene polymorphisms, especially demonstrating protective effects in cardiovascular diseases including heart failure and CHD. The pathogenesis of CHD involves the interaction of multiple factors, and its occurrence and development involve the interaction between genetic susceptibility and environmental risk factors. However, the specific mechanism by which ALDH2 plays a role in this has not yet been clarified. This review summarizes the potential molecular mechanisms between ALDH2 gene polymorphisms and the onset and progression of CHD, aiming to provide theoretical references for the prevention and treatment of CHD.

Key words: coronary heart disease, ethanol, polymorphism, genetic, aldehyde dehydrogenase 2

CLC Number:

R541.4

References 42

[1]	MARTIN S S, ADAY A W, ALMARZOOQ Z I, et al. 2024 Heart disease and stroke statistics:a report of US and global data from the American Heart Association[J]. Circulation,2024, 149(8):e347-e913. doi:10.1161/CIR.0000000000001209.
[2]	国家心血管病中心,中国心血管健康与疾病报告编写组,胡盛寿. 中国心血管健康与疾病报告2023概要[J]. 中国循环杂志, 2024, 39(7):625-660.
	National Center for Cardiovascular Diseases, China Cardiovascular Health and Disease Report Compilation Group, HU S S. Report on cardiovascular health and diseases in China 2023:an updated summary[J]. Chin Circul J, 2024, 39(7):625-660. doi:10.3969/j.issn.1000-3614.2024.07.001.
[3]	TCHEANDJIEU C, ZHU X, HILLIARD A T, et al. Large-scale genome-wide association study of coronary artery disease in genetically diverse populations[J]. Nat Med, 2022, 28(8):1679-1692. doi:10.1038/s41591-022-01891-3.
[4]	ARAGAM K G, JIANG T, GOEL A, et al. Discovery and systematic characterization of risk variants and genes for coronary artery disease in over a million participants[J]. Nat Genet, 2022, 54(12):1803-1815. doi:10.1038/s41588-022-01233-6.
[5]	TAKEUCHI F, YOKOTA M, YAMAMOTO K, et al. Genome-wide association study of coronary artery disease in the Japanese[J]. Eur J Hum Genet, 2012, 20(3):333-40. doi:10.1038/ejhg.2011.184.
[6]	HE Z, GUO Q, LING Y, et al. Aldehyde dehydrogenase 2 rs671 polymorphism and multiple diseases:protocol for a quantitative umbrella review of meta-analyses[J]. Syst Rev, 2022, 11(1):185. doi:10.1186/s13643-022-02050-y.
[7]	袁芳, 杨艳华, 赵鑫扬, 等. 冠心丹参制剂通过miR-330-3p/ALDH2保护大鼠心脏免受缺血/再灌注损伤[J]. 第三军医大学学报, 2021, 43(13):1243-1252.
	YUAN F, YANG Y H, ZHAO X Y, et al. Guanxin Salvia Miltiorrhiza Preparation protects rat cardiomyocytes against ischemia/reperfusion injury through miR-330-3p/ALDH2[J]. Acta Academiae Medicinae Militaris Tertiae, 2021, 43(13):1243-1252. doi:10.16016/j.1000-5404.202101061.
[8]	杨美艳, 韩博, 徐勇, 等. 乙醛脱氢酶2基因型多态性与早发冠心病患者冠状动脉狭窄程度的关系[J]. 解放军医学院学报, 2021, 42(1):7-9,16.
	YANG M Y, HAN B, XU Y, et al. Relationship between ALDH2 polymorphisms and coronary stenosis severity in patients with premature coronary artery disease[J]. Academic Journal of Chinese PLA Medical School, 2021, 42(1):7-9,16. doi:10.3969/j.issn.2095-5227.2021.01.002.
[9]	王波, 王德启, 徐继蕊, 等. 桃叶珊瑚苷调控线粒体乙醛脱氢酶2表达对脂多糖诱导的心肌细胞炎症反应及细胞凋亡的影响[J]. 心肺血管病杂志, 2020, 39(10):1271-1276.
	WANG B, WANG D Q, XU J R, et al. Effect of myrtlein on lipopolysaccharide-induced cardiomyocyte inflammatory response and apoptosis through regulating the expression of mitochondrial aldehyde dehydrogenase 2[J]. Journal of Cardiovascular and Pulmonary Diseases, 2020, 39(10):1271-1276. doi:10.3969/j.issn.1007-5062.2020.10.023.
[10]	LIU H, HU Q, REN K, et al. ALDH2 mitigates LPS-induced cardiac dysfunction,inflammation,and apoptosis through the cGAS/STING pathway[J]. Mol Med, 2023, 29(1):171. doi:10.1186/s10020-023-00769-5.
[11]	ZHANG J, GUO Y, ZHAO X, et al. The role of aldehyde dehydrogenase 2 in cardiovascular disease[J]. Nat Rev Cardiol, 2023, 20(7):495-509. doi:10.1038/s41569-023-00839-5.
[12]	ZHANG J, ZHAO X, GUO Y, et al. Macrophage ALDH2 (aldehyde dehydrogenase 2) stabilizing Rac2 is required for efferocytosis internalization and reduction of atherosclerosis development[J]. Arterioscler Thromb Vasc Biol, 2022, 42(6):700-716. doi:10.1161/ATVBAHA.121.317204.
[13]	MAIUOLO J, OPPEDISANO F, CARRESI C, et al. The generation of nitric oxide from aldehyde dehydrogenase-2:the role of dietary nitrates and their implication in cardiovascular disease management[J]. Int J Mol Sci, 2022, 23(24):15454. doi:10.3390/ijms232415454.
[14]	高必贞, 余将丽, 董晓. 乙醛脱氢酶2基因多态性与稳定型心绞痛患者硝酸甘油疗效的相关性研究进展[J]. 中国医药导报, 2023, 20(27):43-46.
	GAO B Z, YU J L, DONG X. Research progress on correlation between aldehyde dehydrogenase 2 gene polymorphism and the efficacy of nitroglycerin in patients with stable angina pectoris[J]. China Medical Herald, 2023, 20(27):43-46. doi:10.20047/j.issn1673-7210.2023.27.09.
[15]	华德兴, 曾香连, 胡春梅, 等. 广东省韶关地区ALDH2基因调查及人群分布[J]. 海南医学, 2021, 32(20):2623-2625.
	HUA D X, ZENG X L, HU C M, et al. Distribution of ALDH2 genotypes in Shaoguan population[J]. Hainan Medical Journal, 2021, 32(20):2623-2625. doi:10.3969/j.issn.1003-6350.2021.20.010.
[16]	李绒, 李敏, 马聪. 汉族人群中ALDH2 rs671基因多态性与体脂含量的相关性[J]. 中华健康管理学杂志, 2023, 17(6):444-448.
	LI R, LI M, MA C. Relationship between ALDH2 rs671 gene polymorphism and body fat content in Han population[J]. Chinese Journal of Health Management, 2023, 17(6):444-448. doi:10.3760/cma.j.cn115624-20221206-00880.
[17]	吴和弟, 许丽娃, 吉家钗, 等. ALDH2基因多态性与海南地区汉族老年人群冠心病发病风险相关性[J]. 中国老年学杂志, 2022, 42(9):2052-2055.
	WU H D, XU L W, JI J C, et al. The correlation between ALDH2 gene polymorphism and the risk of coronary heart disease in the elderly Han population in Hainan region[J]. Chinese Journal of Gerontology, 2022, 42(9):2052-2055. doi:10.3969/j.issn.1005-9202.2022.09.002.
[18]	YOKOYAMA A, YOKOYAMA T, MATSUI T, et al. Impacts of interactions between ADH1B and ALDH2 genotypes on alcohol flushing,alcohol reeking on the day after drinking,and age distribution in Japanese alcohol-dependent men[J]. Pharmacogenet Genomics, 2020, 30(3):54-60. doi:10.1097/FPC.0000000000000395.
[19]	LU D, WEN Y, LIAO K, et al. Impact of the aldehyde dehydrogenase 2 (ALDH2) gene testing on alcohol drinking behaviors among the Chinese Han population:study protocol of a single-center,open-label,randomized,controlled clinical trial[J]. Trials, 2025, 26(1):147. doi:10.1186/s13063-025-08851-5.
[20]	NG C S, ONG X J, AU M, et al. ALDH 2 polymorphism,alcohol intake and the attributable burden of cancer in East Asia:systematic review,meta-analysis,and modeling study[J]. Ann Epidemiol, 2023, 85:113-120.e20. doi:10.1016/j.annepidem.2023.05.013.
[21]	COOK W K, TAM C C, LUCZAK S E, et al. Alcohol consumption,cardiovascular-related conditions,and ALDH2*2 ethnic group prevalence in Asian Americans[J]. Alcohol Clin Exp Res, 2021, 45(2):418-428. doi:10.1111/acer.14539.
[22]	KOYANAGI Y N, NAKATOCHI M, NAMBA S, et al. Genetic architecture of alcohol consumption identified by a genotype-stratified GWAS and impact on esophageal cancer risk in Japanese people[J]. Sci Adv, 2024, 10(4):eade2780. doi:10.1126/sciadv.ade2780.
[23]	朱青, 尚庆毅, 刘丽平, 等. ALDH2 rs671和ADH1B rs1229984多态性与胃癌、食管癌的相关性研究[J]. 皖南医学院学报, 2024, 43(4):322-326.
	ZHU Q, SHANG Q Y, LIU L P, et al. Associations of ALDH2 rs671 and ADH1B rs1229984 polymorphisms with gastric and esophageal cancer risks[J]. Journal of Wannan Medical College, 2024, 43(4):322-326. doi:10.3969/j.issn.1002-0217.2024.04.004.
[24]	PAN G, ROY B, PALANIYANDI S S. Diabetic aldehyde dehydrogenase 2 mutant (ALDH2*2) mice are more susceptible to cardiac ischemic-reperfusion injury due to 4-hydroxy-2-nonenal induced coronary endothelial cell damage[J]. J Am Heart Assoc, 2021, 10(18):e021140. doi:10.1161/JAHA.121.021140.
[25]	张亚茹, 房芳, 朱浩然, 等. α-硫辛酸通过激活ALDH2减轻酒精诱导的大鼠H9c2细胞损伤[J]. 中国病理生理杂志, 2025, 41(1):1-10.
	ZHANG Y R, FANG F, ZHU H R, et al. α-Lipoic acid alleviates alcohol-induced damage in rat H9c2 cardiomyo-cytes by activating ALDH2[J]. Chinese Journal of Pathophysiology, 2025, 41(1):1-10. doi:10.3969/j.issn.1000-4718.2025.01.001.
[26]	PAPATHEODOROU I, GALATOU E, PANAGIOTIDIS G D, et al. Cardioprotective effects of PPARβ/δ activation against ischemia/reperfusion injury in rat heart are associated with ALDH2 upregulation,amelioration of oxidative stress and preservation of mitochondrial energy production[J]. Int J Mol Sci, 2021, 22(12):6399. doi:10.3390/ijms22126399.
[27]	ROY B, YANG Z, PAN G, et al. Exposure to the dioxin-like pollutant PCB 126 afflicts coronary endothelial cells via increasing 4-hydroxy-2 nonenal:a role for aldehyde dehydrogenase 2[J]. Toxics, 2022, 10(6):328. doi:10.3390/toxics10060328.
[28]	ZHONG S, LI L, ZHANG Y L, et al. Acetaldehyde dehydrogenase 2 interactions with LDLR and AMPK regulate foam cell formation[J]. J Clin Invest, 2019, 129(1):252-267. doi:10.1172/JCI122064.
[29]	BAI Y, WANG M, YANG Y, et al. Inhibition of the miR-193b-3p protects against oxidized low-density lipoprotein-induced HUVECs injury by upregulating ALDH2[J]. Cell Biol Int, 2022, 46(2):192-202. doi:10.1002/cbin.11720.
[30]	HU C, HUANG C, LI J, et al. Causal associations of alcohol consumption with cardiovascular diseases and all-cause mortality among Chinese males[J]. Am J Clin Nutr, 2022, 116(3):771-779. doi:10.1093/ajcn/nqac159.
[31]	RUI H, YU H, CHI K, et al. ALDH2 deficiency augments atherosclerosis through the USP14-cGAS-dependent polarization of proinflammatory macrophages[J]. Redox Biol, 2024,76:103318. doi:10.1016/j.redox.2024.103318.
[32]	XU Y, YUAN Q, CAO S, et al. Aldehyde dehydrogenase 2 inhibited oxidized LDL-induced NLRP3 inflammasome priming and activation via attenuating oxidative stress[J]. Biochem Biophys Res Commun, 2020, 529(4):998-1004. doi:10.1016/j.bbrc.2020.06.075.
[33]	CHANG Y C, LEE H L, YANG W, et al. A common East-Asian ALDH2 mutation causes metabolic disorders and the therapeutic effect of ALDH2 activators[J]. Nat Commun, 2023, 14(1):5971. doi:10.1038/s41467-023-41570-6.
[34]	LI L, ZHONG S, LI R, et al. Aldehyde dehydrogenase 2 and PARP1 interaction modulates hepatic HDL biogenesis by LXRα-mediated ABCA1 expression[J]. JCI Insight, 2022, 7(7):e155869. doi:10.1172/jci.insight.155869.
[35]	HISAMATSU T, MIURA K, TABARA Y, et al. Alcohol consumption and subclinical and clinical coronary heart disease: a Mendelian randomization analysis[J]. Eur J Prev Cardiol, 2022, 29(15):2006-2014. doi: 10.1093/eurjpc/zwac156.
[36]	侯钦钏, 张芮, 李炳宏, 等. 饮酒和乙醛脱氢酶2基因rs671多态性对高血压的影响[J]. 中华高血压杂志, 2023, 31(6):561-567.
	HOU Q C, ZHANG R, LI B H, et al. The effect of alcohol consumption and acetaldehyde dehydrogenase 2 gene rs671 polymorphism on hypertension[J]. Chinese Journal of Hypertension, 2023, 31(6):561-567. doi:10.16439/j.issn.1673-7245.2023.06.008.
[37]	CAO R, FANG D, WANG J, et al. ALDH2 overexpression alleviates high glucose-induced cardiotoxicity by inhibiting NLRP3 inflammasome activation[J]. J Diabetes Res, 2019,2019:4857921. doi:10.1155/2019/4857921.
[38]	格日勒, 吴云, 杨丽云. 乙醛脱氢酶2基因G487A位点多态性与冠心病患者冠状动脉病变程度的关系[J]. 中国循证心血管医学杂志, 2022, 14(4):442-446.
	GERILE, WU Y,YANG L Y. Relationship between of ALDH2 gene G487A polymorphism and severity of coronary artery lesions in patients with coronary heart disease[J]. Chinese Journal of Evidence-Based Cardiovascular Medicine, 2022, 14(4):442-446. doi:10.3969/j.issn.1674-4055.2022.04.14.
[39]	耿旭, 张先林, 王健, 等. ALDH2基因多态性与冠心病患者冠脉病变程度及预后的关系[J]. 华夏医学, 2022, 35(5):13-16.
	GENG X, ZHANG X L, WANG J, et al. Relation between ALDH2 gene polymorphism and the severity of coronary artery disease and the prognosis in patients with coronary heart disease[J]. Acta Medicinae Sinica, 2022, 35(5):13-16. doi:10.19296/j.cnki.1008-2409.2022-05-003.
[40]	MIZUNO Y, HARADA E, KUGIMIYA F, et al. East Asians variant mitochondrial aldehyde dehydrogenase 2 genotype exacerbates nitrate tolerance in patients with coronary spastic angina[J]. Circ J, 2020, 84(3):479-486. doi:10.1253/circj.CJ-19-0989.
[41]	赵敏, 高金全, 吴军, 等. ALDH2单核苷酸多态性(rs671)与冠心病稳定型心绞痛患者硝酸甘油疗效的关系研究[J]. 中国煤炭工业医学杂志, 2024, 27(1):68-72.
	ZHAO M, GAO J Q, WU J, et al. Relationship between single nucleotide polymorphisms of ALDH2(rs671)and the efficacy of glyceryl trinitrate in patients with stable angina pectoris of coronary heart disease[J]. Chinese Journal of Coal Industry Medicine, 2024, 27(1):68-72. doi:10.11723/mtgyyx1007-9564202401014.
[42]	中华人民共和国国家卫生和计划生育委员会. 药物代谢酶和药物作用靶点基因检测技术指南(试行)概要[J]. 实用器官移植电子杂志, 2015, 3(5):257-267.
	National Health and Family Planning Commission of the People's Republic of China. Summary of the technical guidelines for the detection of drug-metabolizing enzymes and drug action target genes (trial)[J]. Practical Journal of Organ Transplantation(Electronic Version), 2015, 3(5):257-267. doi:10.3969/j.issn.2095-5332.2015.05.001.