Yonsei Med J.  2017 Jul;58(4):689-696. 10.3349/ymj.2017.58.4.689.

Alcohol Consumption, Aldehyde Dehydrogenase 2 Gene Polymorphisms, and Cardiovascular Health in Korea

Affiliations
  • 1Department of Public Health Sciences, BK21PLUS Program in Embodiment: Health-Society Interaction, Graduate School, Korea University, Seoul, Korea. mjshin@korea.ac.kr
  • 2MRC Integrative Epidemiology Unit, School of Social & Community Medicine, University of Bristol, Bristol, UK.

Abstract

Alcohol consumption is a serious health issue in Korea in terms of the amount consumed and the behavior related to its consumption. Aldehyde dehydrogenase 2 (ALDH2) is a key enzyme in alcohol metabolism that degrades acetaldehyde to nontoxic acetic acid. The enzyme is coded by the ALDH2 gene, which is commonly polymorphic in East Asian populations. A point mutation in the ALDH2 gene (the rs671 allele) yields an inactive form of ALDH2 that causes acetaldehyde accumulation in the body after alcohol consumption, thereby inhibiting normal alcohol metabolism. Individuals who are homozygous for polymorphism in ALDH2 tend to refrain from drinking alcohol, decreasing their chances of developing alcoholism and exposure to the associated risks. Mendelian randomization (MR) studies have demonstrated that alcohol consumption predicted by ALDH2 genotype is causally related to cardiovascular risks. Moreover, recent MR studies suggest that the ALDH2 variant has mechanistic effects on some disease outcomes or mortality through increased blood levels of acetaldehyde, showing differences therein between heterozygotes (ALDH2*2*2) and homozygotes (ALDH2*1*2) in those who consume alcohol. Accordingly, consideration of ALDH2 genotype in alcohol prevention programs is warranted. In conclusion, strategies that incorporate genetic information and provide an evidential basis from which to help people make informed decisions on alcohol consumption are urgently required.

Keyword

Alcohol; aldehyde dehydrogenase 2; Mendelian randomization analysis; guidelines

MeSH Terms

Alcohol Drinking/epidemiology/*genetics
Aldehyde Dehydrogenase, Mitochondrial/*genetics
Cardiovascular Diseases/*enzymology/*genetics
*Genetic Predisposition to Disease
Humans
Mendelian Randomization Analysis
*Polymorphism, Genetic
Republic of Korea
Aldehyde Dehydrogenase, Mitochondrial

Figure

  • Fig. 1 Alcohol metabolism according to genetic polymorphisms. (A) Aldehyde dehydrogenase 2 (ALDH2) and alcohol dehydrogenase 1B (ADH1B) are involved in alcohol metabolism. Generally, ALDH2 variants have a greater influence on alcohol intake than ADH1B variants in East Asians. (B) ALDH2 variants mainly exist in East Asian populations. Adapted from Cho, et al. Sci Rep 2015;5:18422.6

  • Fig. 2 Scheme of the Mendelian randomization approach. The scheme of the Mendelian randomization approach. (A) This method uses a genetic variant, which proxies for exposure that is expected to be related to the outcome. (B) Using the Mendelian randomization approach, the causal effects of alcohol intake on cardiovascular outcomes can be investigated while controlling confounders and reverse causation. ALDH2, aldehyde dehydrogenase 2.


Reference

1. Korea Centers for Disease Control and Prevention. Development of surveillance system on alcohol consumption and alcohol-related harms based on community health survey. Cheongju: Korea Centers for Disease Control and Prevention;2011.
2. Ministry of Health and Welfare. Korea Centers for Disease Control and Prevention. Korea Health Statistics 2013: Korea National Health and Nutrition Examination Survey (KNHANES VI-1). Cheongju: Korea Centers for Disease Control and Prevention;2014.
3. World Health Organization. Global strategy to reduce the harmful use of alcohol. Geneva: World Health Organization;2010.
4. Foxcroft DR, Lister-Sharp D, Lowe G. Alcohol misuse prevention for young people: a systematic review reveals methodological concerns and lack of reliable evidence of effectiveness. Addiction. 1997; 92:531–537. PMID: 9219376.
Article
5. Chen YC, Peng GS, Wang MF, Tsao TP, Yin SJ. Polymorphism of ethanol-metabolism genes and alcoholism: correlation of allelic variations with the pharmacokinetic and pharmacodynamic consequences. Chem Biol Interact. 2009; 178:2–7. PMID: 19014920.
Article
6. Cho Y, Shin SY, Won S, Relton CL, Davey Smith G, Shin MJ. Alcohol intake and cardiovascular risk factors: a Mendelian randomisation study. Sci Rep. 2015; 5:18422. PMID: 26687910.
Article
7. Boccia S, Hashibe M, Gallì P, De Feo E, Asakage T, Hashimoto T, et al. Aldehyde dehydrogenase 2 and head and neck cancer: a meta-analysis implementing a Mendelian randomization approach. Cancer Epidemiol Biomarkers Prev. 2009; 18:248–254. PMID: 19124505.
Article
8. Lewis SJ, Smith GD. Alcohol, ALDH2, and esophageal cancer: a meta-analysis which illustrates the potentials and limitations of a Mendelian randomization approach. Cancer Epidemiol Biomarkers Prev. 2005; 14:1967–1971. PMID: 16103445.
Article
9. Yokoyama A, Omori T, Yokoyama T. Alcohol and aldehyde dehydrogenase polymorphisms and a new strategy for prevention and screening for cancer in the upper aerodigestive tract in East Asians. Keio J Med. 2010; 59:115–130. PMID: 21187698.
Article
10. He L, Deng T, Luo H. Aldehyde dehydrogenase 2 (ALDH2) polymorphism and the risk of alcoholic liver cirrhosis among East Asians: a meta-analysis. Yonsei Med J. 2016; 57:879–884. PMID: 27189280.
Article
11. Taylor AE, Lu F, Carslake D, Hu Z, Qian Y, Liu S, et al. Exploring causal associations of alcohol with cardiovascular and metabolic risk factors in a Chinese population using Mendelian randomization analysis. Sci Rep. 2015; 5:14005. PMID: 26364564.
Article
12. Enomoto N, Takase S, Yasuhara M, Takada A. Acetaldehyde metabolism in different aldehyde dehydrogenase-2 genotypes. Alcohol Clin Exp Res. 1991; 15:141–144. PMID: 2024727.
Article
13. Matsumoto C, Miedema MD, Ofman P, Gaziano JM, Sesso HD. An expanding knowledge of the mechanisms and effects of alcohol consumption on cardiovascular disease. J Cardiopulm Rehabil Prev. 2014; 34:159–171. PMID: 24667667.
Article
14. Knott C, Bell S, Britton A. Alcohol consumption and the risk of type 2 diabetes: a systematic review and dose-response metaanalysis of more than 1.9 million individuals from 38 observational studies. Diabetes Care. 2015; 38:1804–1812. PMID: 26294775.
Article
15. Corrao G, Rubbiati L, Bagnardi V, Zambon A, Poikolainen K. Alcohol and coronary heart disease: a meta-analysis. Addiction. 2000; 95:1505–1523. PMID: 11070527.
Article
16. Freiberg MS, Samet JH. Alcohol and coronary heart disease: the answer awaits a randomized controlled trial. Circulation. 2005; 112:1379–1381. PMID: 16145011.
17. Ng Fat L, Cable N, Marmot MG, Shelton N. Persistent long-standing illness and non-drinking over time, implications for the use of lifetime abstainers as a control group. J Epidemiol Community Health. 2014; 68:71–77. PMID: 24166583.
Article
18. Ronksley PE, Brien SE, Turner BJ, Mukamal KJ, Ghali WA. Association of alcohol consumption with selected cardiovascular disease outcomes: a systematic review and meta-analysis. BMJ. 2011; 342:d671. PMID: 21343207.
Article
19. Park JE, Choi TY, Ryu Y, Cho SI. The relationship between mild alcohol consumption and mortality in Koreans: a systematic review and meta-analysis. BMC Public Health. 2015; 15:918. PMID: 26385795.
Article
20. Holmes MV, Dale CE, Zuccolo L, Silverwood RJ, Guo Y, Ye Z, et al. Association between alcohol and cardiovascular disease: Mendelian randomisation analysis based on individual participant data. BMJ. 2014; 349:g4164. PMID: 25011450.
21. International Agency for Research on Cancer. Agents classified by the IARC Monographs, volumes 1-104. accessed on 2017 January 5. Available at: http://monographs.iarc.fr/ENG/Classification/ClassificationsAlphaOrder.pdf.
22. Scoccianti C, Cecchini M, Anderson AS, Berrino F, Boutron-Ruault MC, Espina C, et al. European code against cancer 4th edition: alcohol drinking and cancer. Cancer Epidemiol. 2015; 39(Suppl 1):S67–S74. PMID: 26115567.
Article
23. Korea Centers for Disease Control and Prevention. National Cancer Center. Guideline for prevension of cancer (Korean). Cheongju: Korea Centers for Disease Control and Prevention;2016.
24. Buscemi L, Turchi C. An overview of the genetic susceptibility to alcoholism. Med Sci Law. 2011; 51(Suppl 1):S2–S6. PMID: 22021628.
Article
25. Dragan WŁ, Oniszczenko W, Czerski PM, Dmitrzak-Weglarz M. [Family-based association study of dopaminergic genes polymorphisms and EAS temperamental traits]. Psychiatr Pol. 2013; 47:185–195. PMID: 23888754.
26. Heath AC, Bucholz KK, Madden PA, Dinwiddie SH, Slutske WS, Bierut LJ, et al. Genetic and environmental contributions to alcohol dependence risk in a national twin sample: consistency of findings in women and men. Psychol Med. 1997; 27:1381–1396. PMID: 9403910.
Article
27. Bujarski S, Lau AS, Lee SS, Ray LA. Genetic and environmental predictors of alcohol use in Asian American young adults. J Stud Alcohol Drugs. 2015; 76:690–699. PMID: 26402349.
Article
28. Wall TL, Luczak SE, Hiller-Sturmhöfel S. Biology, genetics, and environment: underlying factors influencing alcohol metabolism. Alcohol Res. 2016; 38:59–68. PMID: 27163368.
29. Eng MY, Luczak SE, Wall TL. ALDH2, ADH1B, and ADH1C genotypes in Asians: a literature review. Alcohol Res Health. 2007; 30:22–27. PMID: 17718397.
30. Luczak SE, Pandika D, Shea SH, Eng MY, Liang T, Wall TL. ALDH2 and ADH1B interactions in retrospective reports of low-dose reactions and initial sensitivity to alcohol in Asian American college students. Alcohol Clin Exp Res. 2011; 35:1238–1245. PMID: 21355870.
Article
31. Wall TL. Genetic associations of alcohol and aldehyde dehydrogenase with alcohol dependence and their mechanisms of action. Ther Drug Monit. 2005; 27:700–703. PMID: 16404797.
Article
32. Baik I, Cho NH, Kim SH, Han BG, Shin C. Genome-wide association studies identify genetic loci related to alcohol consumption in Korean men. Am J Clin Nutr. 2011; 93:809–816. PMID: 21270382.
Article
33. Dickson PA, James MR, Heath AC, Montgomery GW, Martin NG, Whitfield JB, et al. Effects of variation at the ALDH2 locus on alcohol metabolism, sensitivity, consumption, and dependence in Europeans. Alcohol Clin Exp Res. 2006; 30:1093–1100. PMID: 16792555.
Article
34. Kim DJ, Choi IG, Park BL, Lee BC, Ham BJ, Yoon S, et al. Major genetic components underlying alcoholism in Korean population. Hum Mol Genet. 2008; 17:854–858. PMID: 18056758.
Article
35. Hendershot CS, Neighbors C, George WH, McCarthy DM, Wall TL, Liang T, et al. ALDH2, ADH1B and alcohol expectancies: integrating genetic and learning perspectives. Psychol Addict Behav. 2009; 23:452–463. PMID: 19769429.
Article
36. Duranceaux NC, Schuckit MA, Luczak SE, Eng MY, Carr LG, Wall TL. Ethnic differences in level of response to alcohol between Chinese Americans and Korean Americans. J Stud Alcohol Drugs. 2008; 69:227–234. PMID: 18299763.
Article
37. Li H, Borinskaya S, Yoshimura K, Kal'ina N, Marusin A, Stepanov VA, et al. Refined geographic distribution of the oriental ALDH2*504Lys (nee 487Lys) variant. Ann Hum Genet. 2009; 73(Pt 3):335–345. PMID: 19456322.
38. Yukawa Y, Muto M, Hori K, Nagayoshi H, Yokoyama A, Chiba T, et al. Combination of ADH1B*2/ALDH2*2 polymorphisms alters acetaldehyde-derived DNA damage in the blood of Japanese alcoholics. Cancer Sci. 2012; 103:1651–1655. PMID: 22703580.
Article
39. Paik IH, Lee C, Lee SJ, Lee CU, Kim JJ, Jun TY, et al. Genetic frequencies of aldehyde dehydrogenase 2 in Korea patients with alcohol dependence. J Korean Neuropsychiatr Assoc. 1998; 37:149–158.
40. Paik K. The studies on the differences in personality trait by aldehyde dehydrogenase-I genotype variances in Korean male alcoholics. J Korean Neuropsychiatr Assoc. 1995; 34:15–26.
41. Hashimoto M, Watanabe M, Uematsu Y, Hattori S, Miyai N, Utsumi M, et al. Relationships of alcohol dehydrogenase 1B (ADH1B) and aldehyde dehydrogenase 2 (ALDH2) genotypes with alcohol sensitivity, drinking behavior and problem drinking in Japanese older men. Environ Health Prev Med. 2016; 21:138–148. PMID: 26825972.
Article
42. Mulligan MK, Ponomarev I, Hitzemann RJ, Belknap JK, Tabakoff B, Harris RA, et al. Toward understanding the genetics of alcohol drinking through transcriptome meta-analysis. Proc Natl Acad Sci U S A. 2006; 103:6368–6373. PMID: 16618939.
Article
43. Kim SW, Bae KY, Shin HY, Kim JM, Shin IS, Youn T, et al. The role of acetaldehyde in human psychomotor function: a double-blind placebo-controlled crossover study. Biol Psychiatry. 2010; 67:840–845. PMID: 19914598.
Article
44. Lee B, Nam B, Seo JS, Jang S, Lee S, Yi SH. Elimination rate and pharmacokinetics of alcohol in Korean healthy male adults. J Korean Neuropsychiatr Assoc. 2015; 54:427–434.
Article
45. Kawano Y. Physio-pathological effects of alcohol on the cardiovascular system: its role in hypertension and cardiovascular disease. Hypertens Res. 2010; 33:181–191. PMID: 20075936.
Article
46. Brooks PJ, Enoch MA, Goldman D, Li TK, Yokoyama A. The alcohol flushing response: an unrecognized risk factor for esophageal cancer from alcohol consumption. PLoS Med. 2009; 6:e50. PMID: 19320537.
Article
47. Assanangkornchai S, Noi-pha K, Saunders JB, Ratanachaiyavong S. Aldehyde dehydrogenase 2 genotypes, alcohol flushing symptoms and drinking patterns in Thai men. Psychiatry Res. 2003; 118:9–17. PMID: 12759156.
Article
48. Crabb DW, Edenberg HJ, Bosron WF, Li TK. Genotypes for aldehyde dehydrogenase deficiency and alcohol sensitivity. The inactive ALDH2(2) allele is dominant. J Clin Invest. 1989; 83:314–316. PMID: 2562960.
Article
49. Kim JM, Shin IS, Kim SW, Lee H, Yoon BH, Yoon JS. Relationships between Lifetime alcohol consumption and cognitive function in an elderly population: effect modification by level of education. Korean J Psychopharmacol. 2003; 14:239–243.
50. Sin IS, Yoon JS, Kim H, Lee HY, Yoon BH, Lee H, et al. Effects of alcohol on neurocognitive function, psychomotor performance and subjective response in Koreans with different ALDH2 genotypes. J Korean Soc Biol Psychiatry. 1999; 6:176–188.
51. Zhao Y, Wang C. Glu504Lys single nucleotide polymorphism of aldehyde dehydrogenase 2 gene and the risk of human diseases. Biomed Res Int. 2015; 2015:174050. PMID: 26491656.
Article
52. Gu JY, Li LW. ALDH2 Glu504Lys polymorphism and susceptibility to coronary artery disease and myocardial infarction in East Asians: a meta-analysis. Arch Med Res. 2014; 45:76–83. PMID: 24333098.
Article
53. Wang Q, Zhou S, Wang L, Lei M, Wang Y, Miao C, et al. ALDH2 rs671 Polymorphism and coronary heart disease risk among Asian populations: a meta-analysis and meta-regression. DNA Cell Biol. 2013; 32:393–399. PMID: 23697560.
54. Jia K, Wang H, Dong P. Aldehyde dehydrogenase 2 (ALDH2) Glu-504Lys polymorphism is associated with hypertension risk in Asians: a meta-analysis. Int J Clin Exp Med. 2015; 8:10767–10772. PMID: 26379870.
55. Rehm J, Shield KD, Roerecke M, Gmel G. Modelling the impact of alcohol consumption on cardiovascular disease mortality for comparative risk assessments: an overview. BMC Public Health. 2016; 16:363. PMID: 27121289.
Article
56. Chen L, Smith GD, Harbord RM, Lewis SJ. Alcohol intake and blood pressure: a systematic review implementing a Mendelian randomization approach. PLoS Med. 2008; 5:e52. PMID: 18318597.
Article
57. Ota M, Hisada A, Lu X, Nakashita C, Masuda S, Katoh T. Associations between aldehyde dehydrogenase 2 (ALDH2) genetic polymorphisms, drinking status, and hypertension risk in Japanese adult male workers: a case-control study. Environ Health Prev Med. 2016; 21:1–8. PMID: 26318866.
Article
58. Yin G, Naito M, Wakai K, Morita E, Kawai S, Hamajima N, et al. ALDH2 polymorphism is associated with fasting blood glucose through alcohol consumption in Japanese men. Nagoya J Med Sci. 2016; 78:183–193. PMID: 27303105.
59. Jo SA, Kim EK, Park MH, Han C, Park HY, Jang Y, et al. A Glu487Lys polymorphism in the gene for mitochondrial aldehyde dehydrogenase 2 is associated with myocardial infarction in elderly Korean men. Clin Chim Acta. 2007; 382:43–47. PMID: 17459359.
Article
60. Eom SY, Zhang YW, Kim SH, Choe KH, Lee KY, Park JD, et al. Influence of NQO1, ALDH2, and CYP2E1 genetic polymorphisms, smoking, and alcohol drinking on the risk of lung cancer in Koreans. Cancer Causes Control. 2009; 20:137–145. PMID: 18798003.
Article
61. Smith GD, Ebrahim S. ‘Mendelian randomization’: can genetic epidemiology contribute to understanding environmental determinants of disease? Int J Epidemiol. 2003; 32:1–22. PMID: 12689998.
62. Shin C, Kwack K, Cho NH, Kim SH, Baik I. Sex-specific differences in the association of a common aldehyde dehydrogenase 2 gene polymorphism and alcohol consumption with stroke risk in a Korean population: a prospective cohort study. Nutr Res Pract. 2015; 9:79–86. PMID: 25671072.
Article
63. Yun KE, Chang Y, Yun SC, Davey Smith G, Ryu S, Cho SI, et al. Alcohol and coronary artery calcification: an investigation using alcohol flushing as an instrumental variable. Int J Epidemiol. 2017; 1. 10. [Epub ahead of print]. DOI: 10.1093/ije/dyw237.
Article
64. Zuccolo L, Holmes MV. Commentary: Mendelian randomization-inspired causal inference in the absence of genetic data. Int J Epidemiol. 2016; 12. 26. [Epub ahead of print]. DOI: 10.1093/ije/dyw327.
Article
65. Alcohol Project Supporting Committee. Alcohol statistics white paper. Goyang: Alcohol Project Supporting Committee;2010.
66. Oberbeck N, Langevin F, King G, de Wind N, Crossan GP, Patel KJ. Maternal aldehyde elimination during pregnancy preserves the fetal genome. Mol Cell. 2014; 55:807–817. PMID: 25155611.
Article
67. Yokoyama A, Kumagai Y, Yokoyama T, Omori T, Kato H, Igaki H, et al. Health risk appraisal models for mass screening for esophageal and pharyngeal cancer: an endoscopic follow-up study of cancer-free Japanese men. Cancer Epidemiol Biomarkers Prev. 2009; 18:651–655. PMID: 19190142.
Article
68. Shin HY, Shin IS, Yoon JS. ALDH2 genotype-associated differences in the acute effects of alcohol on P300, psychomotor performance, and subjective response in healthy young Korean men: a double-blind placebo-controlled crossover study. Hum Psychopharmacol. 2006; 21:159–166. PMID: 16565959.
Article
69. Jee YH, Lee SJ, Jung KJ, Jee SH. Alcohol intake and serum glucose levels from the perspective of a mendelian randomization design: the KCPS-II biobank. PLoS One. 2016; 11:e0162930. PMID: 27632197.
Article
70. Xu L, Jiang CQ, Cheng KK, Au Yeung SL, Zhang WS, Lam TH, et al. Alcohol use and gamma-glutamyltransferase using a Mendelian randomization design in the Guangzhou Biobank Cohort Study. PLoS One. 2015; 10:e0137790. PMID: 26356841.
Article
71. Au Yeung SL, Jiang C, Long M, Cheng KK, Liu B, Zhang W, et al. Evaluation of moderate alcohol use with QT Interval and heart rate using Mendelian randomization analysis among older Southern Chinese men in the Guangzhou Biobank Cohort Study. Am J Epidemiol. 2015; 182:320–327. PMID: 26153479.
Article
72. Au Yeung SL, Jiang C, Cheng KK, Cowling BJ, Liu B, Zhang W, et al. Moderate alcohol use and cardiovascular disease from Mendelian randomization. PLoS One. 2013; 8:e68054. PMID: 23874492.
Article
73. Au Yeung SL, Jiang CQ, Cheng KK, Liu B, Zhang WS, Lam TH, et al. Evaluation of moderate alcohol use and cognitive function among men using a Mendelian randomization design in the Guangzhou Biobank Cohort Study. Am J Epidemiol. 2012; 175:1021–1028. PMID: 22302076.
Article
74. Tabara Y, Arai H, Hirao Y, Takahashi Y, Setoh K, Kawaguchi T, et al. The causal effects of alcohol on lipoprotein subfraction and triglyceride levels using a Mendelian randomization analysis: The Nagahama Study. Atherosclerosis. 2017; 257:22–28. PMID: 28038378.
Article
75. Tabara Y, Ueshima H, Takashima N, Hisamatsu T, Fujiyoshi A, Zaid M, et al. Mendelian randomization analysis in three Japanese populations supports a causal role of alcohol consumption in lowering low-density lipid cholesterol levels and particle numbers. Atherosclerosis. 2016; 254:242–248. PMID: 27575649.
Article
Full Text Links
  • YMJ
Actions
Cited
CITED
export Copy
Close
Share
  • Twitter
  • Facebook
Similar articles
Copyright © 2024 by Korean Association of Medical Journal Editors. All rights reserved.     E-mail: koreamed@kamje.or.kr