Nutr Res Pract.  2015 Feb;9(1):79-86. 10.4162/nrp.2015.9.1.79.

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

• Shin C
• Kwack K
• Cho NH
• Kim SH
• Baik I

• KMID: 2313813
• DOI: http://doi.org/10.4162/nrp.2015.9.1.79

Abstract

BACKGROUND/OBJECTIVES
It is well-known that alcohol consumption is associated with stroke risk as well as with aldehyde dehydrogenase 2 gene (ALDH2) polymorphisms. However, it is unclear whether ALDH2 polymorphisms are associated with stroke risk independent of alcohol consumption and whether such association is modified by sex. We evaluated sex-specific associations of a common ALDH2 polymorphism and alcohol consumption with stroke risk in a Korean population.
SUBJECTS/METHODS
We conducted a prospective cohort study involving 8,465 men and women, aged 40-69 years and free of stroke between June, 2001 and January, 2003, and followed for the development of stroke. We identified new cases of stroke, which were self-reported or ascertained from vital registration data. Based on genome-wide association data, we selected a single-nucleotide polymorphism (rs2074356), which shows high linkage disequilibrium with the functional polymorphism of ALDH2. We conducted Cox proportional hazards regression analysis considering potential risk factors collected from a baseline questionnaire.
RESULTS
Over the median follow-up of 8 years, 121 cases of stroke were identified. Carrying the wild-type allele of the ALDH2 polymorphism increased stroke risk among men. The multivariate hazard ratio [95% confidence interval] of stroke was 2.02 [1.03-3.99] for the wild-type allele compared with the mutant alleles, but the association was attenuated after controlling for alcohol consumption. Combinations of the wild-type allele and other risk factors of stroke, such as old age, diabetes mellitus, and habitual snoring, synergistically increased the risk among men. Among women, however, the ALDH2 polymorphism was not associated with stroke risk.
CONCLUSIONS
The prospective cohort study showed a significant association between a common ALDH2 polymorphism and stroke risk in Korean men, but not in Korean women, and also demonstrated that men with genetic disadvantages gain more risk when having risk factors of stroke. Thus, these men may need to make more concerted efforts to control modifiable risk factors of stroke.

Keyword

ALDH2 polymorphism; alcohol consumption; stroke; prospective study

MeSH Terms

Alcohol Drinking*
Aldehyde Dehydrogenase*
Alleles
Cohort Studies*
Diabetes Mellitus
Female
Follow-Up Studies
Humans
Linkage Disequilibrium
Male
Prospective Studies*
Surveys and Questionnaires
Risk Factors
Snoring
Stroke*
Aldehyde Dehydrogenase

Reference

1. Thomasson HR, Crabb DW, Edenberg HJ, Li TK. Alcohol and aldehyde dehydrogenase polymorphisms and alcoholism. Behav Genet. 1993; 23:131–136.

2. Takeuchi F, Isono M, Nabika T, Katsuya T, Sugiyama T, Yamaguchi S, Kobayashi S, Ogihara T, Yamori Y, Fujioka A, Kato N. Confirmation of ALDH2 as a Major locus of drinking behavior and of its variants regulating multiple metabolic phenotypes in a Japanese population. Circ J. 2011; 75:911–918.

3. 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.

4. Yang SJ, Yokoyama A, Yokoyama T, Huang YC, Wu SY, Shao Y, Niu J, Wang J, Liu Y, Zhou XQ, Yang CX. Relationship between genetic polymorphisms of ALDH2 and ADH1B and esophageal cancer risk: a meta-analysis. World J Gastroenterol. 2010; 16:4210–4220.

5. Duell EJ, Sala N, Travier N, Muñoz X, Boutron-Ruault MC, Clavel-Chapelon F, Barricarte A, Arriola L, Navarro C, Sánchez-Cantalejo E, Quirós JR, Krogh V, Vineis P, Mattiello A, Tumino R, Khaw KT, Wareham N, Allen NE, Peeters PH, Numans ME, Bueno-de-Mesquita HB, van Oijen MG, Bamia C, Benetou V, Trichopoulos D, Canzian F, Kaaks R, Boeing H, Bergmann MM, Lund E, Ehrnström R, Johansen D, Hallmans G, Stenling R, Tjønneland A, Overvad K, Ostergaard JN, Ferrari P, Fedirko V, Jenab M, Nesi G, Riboli E, González CA. Genetic variation in alcohol dehydrogenase (ADH1A, ADH1B, ADH1C, ADH7) and aldehyde dehydrogenase (ALDH2), alcohol consumption and gastric cancer risk in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. Carcinogenesis. 2012; 33:361–367.

6. Hiura Y, Tabara Y, Kokubo Y, Okamura T, Miki T, Tomoike H, Iwai N. A genome-wide association study of hypertension-related phenotypes in a Japanese population. Circ J. 2010; 74:2353–2359.

7. Chang YC, Chiu YF, Lee IT, Ho LT, Hung YJ, Hsiung CA, Quertermous T, Donlon T, Lee WJ, Lee PC, Chen CH, Mochly-Rosen D, Chuang LM. Common ALDH2 genetic variants predict development of hypertension in the SAPPHIRe prospective cohort: gene-environmental interaction with alcohol consumption. BMC Cardiovasc Disord. 2012; 12:58.

8. Suzuki Y, Muramatsu T, Taniyama M, Atsumi Y, Kawaguchi R, Higuchi S, Hosokawa K, Asahina T, Murata C, Matsuoka K. Association of aldehyde dehydrogenase with inheritance of NIDDM. Diabetologia. 1996; 39:1115–1118.

9. Takagi S, Iwai N, Yamauchi R, Kojima S, Yasuno S, Baba T, Terashima M, Tsutsumi Y, Suzuki S, Morii I, Hanai S, Ono K, Baba S, Tomoike H, Kawamura A, Miyazaki S, Nonogi H, Goto Y. Aldehyde dehydrogenase 2 gene is a risk factor for myocardial infarction in Japanese men. Hypertens Res. 2002; 25:677–681.

10. Jo SA, Kim EK, Park MH, Han C, Park HY, Jang Y, Song BJ, Jo I. 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.

11. Guo YJ, Chen L, Bai YP, Li L, Sun J, Zhang GG, Yang TL, Xia J, Li YJ, Chen XP. The ALDH2 Glu504Lys polymorphism is associated with coronary artery disease in Han Chinese: Relation with endothelial ADMA levels. Atherosclerosis. 2010; 211:545–550.

12. Chen CH, Sun L, Mochly-Rosen D. Mitochondrial aldehyde dehydrogenase and cardiac diseases. Cardiovasc Res. 2010; 88:51–57.

13. Yao CT, Cheng CA, Wang HK, Chiu SW, Chen YC, Wang MF, Yin SJ, Peng GS. The role of ALDH2 and ADH1B polymorphism in alcohol consumption and stroke in Han Chinese. Hum Genomics. 2011; 5:569–576.

14. Reynolds K, Lewis B, Nolen JD, Kinney GL, Sathya B, He J. Alcohol consumption and risk of stroke: a meta-analysis. JAMA. 2003; 289:579–588.

15. Lee JY, Lee BS, Shin DJ, Park KW, Shin YA, Kim KJ, Heo L, Lee JY, Kim YK, Kim YJ, Hong CB, Lee SH, Yoon D, Ku HJ, Oh IY, Kim BJ, Lee J, Park SJ, Kim J, Kawk HK, Lee JE, Park HK, Lee JE, Nam HY, Park HY, Shin C, Yokota M, Asano H, Nakatochi M, Matsubara T, Kitajima H, Yamamoto K, Kim HL, Han BG, Cho MC, Jang Y, Kim HS, Park JE, Lee JY. A genome-wide association study of a coronary artery disease risk variant. J Hum Genet. 2013; 58:120–126.

16. Cho YS, Go MJ, Kim YJ, Heo JY, Oh JH, Ban HJ, Yoon D, Lee MH, Kim DJ, Park M, Cha SH, Kim JW, Han BG, Min H, Ahn Y, Park MS, Han HR, Jang HY, Cho EY, Lee JE, Cho NH, Shin C, Park T, Park JW, Lee JK, Cardon L, Clarke G, McCarthy MI, Lee JY, Lee JK, Oh B, Kim HL. A large-scale genome-wide association study of Asian populations uncovers genetic factors influencing eight quantitative traits. Nat Genet. 2009; 41:527–534.

17. Bierut LJ, Goate AM, Breslau N, Johnson EO, Bertelsen S, Fox L, Agrawal A, Bucholz KK, Grucza R, Hesselbrock V, Kramer J, Kuperman S, Nurnberger J, Porjesz B, Saccone NL, Schuckit M, Tischfield J, Wang JC, Foroud T, Rice JP, Edenberg HJ. ADH1B is associated with alcohol dependence and alcohol consumption in populations of European and African ancestry. Mol Psychiatry. 2012; 17:445–450.

18. Li H, Borinskaya S, Yoshimura K, Kal'ina N, Marusin A, Stepanov VA, Qin Z, Khaliq S, Lee MY, Yang Y, Mohyuddin A, Gurwitz D, Mehdi SQ, Rogaev E, Jin L, Yankovsky NK, Kidd JR, Kidd KK. Refined geographic distribution of the oriental ALDH2 * 504Lys (nee 487Lys) variant. Ann Hum Genet. 2009; 73:335–345.

19. Takeshita T, Morimoto K. Self-reported alcohol-associated symptoms and drinking behavior in three ALDH2 genotypes among Japanese university students. Alcohol Clin Exp Res. 1999; 23:1065–1069.

20. Nagasawa H, Wada M, Arawaka S, Kawanami T, Kurita K, Daimon M, Adachi M, Hosoya T, Emi M, Muramatsu M, Kato T. A polymorphism of the aldehyde dehydrogenase 2 gene is a risk factor for multiple lacunar infarcts in Japanese men: the Takahata Study. Eur J Neurol. 2007; 14:428–434.

21. Zee RY, Ridker PM, Cook NR. Prospective evaluation of the alcohol dehydrogenase gamma1/gamma2 gene polymorphism and risk of stroke. Stroke. 2004; 35:e39–e42.

22. Drogan D, Sheldrick AJ, Schütze M, Knüppel S, Andersohn F, di Giuseppe R, Herrmann B, Willich SN, Garbe E, Bergmann MM, Boeing H, Weikert C. Alcohol consumption, genetic variants in alcohol deydrogenases, and risk of cardiovascular diseases: a prospective study and meta-analysis. PLoS One. 2012; 7:e32176.

23. Riemann R, Volk R, Müller A, Herzog M. The influence of nocturnal alcohol ingestion on snoring. Eur Arch Otorhinolaryngol. 2010; 267:1147–1156.

24. Koskenvuo M, Kaprio J, Telakivi T, Partinen M, Heikkilä K, Sarna S. Snoring as a risk factor for ischaemic heart disease and stroke in men. Br Med J (Clin Res Ed). 1987; 294:16–19.

25. Hu FB, Willett WC, Manson JE, Colditz GA, Rimm EB, Speizer FE, Hennekens CH, Stampfer MJ. Snoring and risk of cardiovascular disease in women. J Am Coll Cardiol. 2000; 35:308–313.

26. Sands M, Loucks EB, Lu B, Carskadon MA, Sharkey K, Stefanick M, Ockene J, Shah N, Hairston KG, Robinson J, Limacher M, Hale L, Eaton CB. Self-reported snoring and risk of cardiovascular disease among postmenopausal women (from the Women's Health Initiative). Am J Cardiol. 2013; 111:540–546.

27. Chen CH, Budas GR, Churchill EN, Disatnik MH, Hurley TD, Mochly-Rosen D. Activation of aldehyde dehydrogenase-2 reduces ischemic damage to the heart. Science. 2008; 321:1493–1495.

28. Mackenzie IS, Maki-Petaja KM, McEniery CM, Bao YP, Wallace SM, Cheriyan J, Monteith S, Brown MJ, Wilkinson IB. Aldehyde dehydrogenase 2 plays a role in the bioactivation of nitroglycerin in humans. Arterioscler Thromb Vasc Biol. 2005; 25:1891–1895.

29. Gorelick PB. Alcohol and stroke. Stroke. 1987; 18:268–271.