Open Access

The role of ALDH2 and ADH1Bpolymorphism in alcohol consumption and stroke in Han Chinese

  • Chung-Tay Yao1,
  • Chun-An Cheng2,
  • Hsu-Kun Wang3,
  • Shao-Wen Chiu4,
  • Yi-Chyan Chen5,
  • Ming-Fang Wang6,
  • Shih-Jiun Yin6 and
  • Giia-Sheun Peng2Email author
Human Genomics20115:569

DOI: 10.1186/1479-7364-5-6-569

Received: 18 June 2011

Accepted: 18 June 2011

Published: 1 October 2011

Abstract

The genes encoding the enzymes for metabolising alcohol dehydrogenase 1B (ADH1B) and aldehyde dehydrogenase 2 (ALDH2) -- exhibit genetic polymorphism and ethnic variations. Although the ALDH2*2 variant allele has been widely accepted as protecting against the development of alcoholism in Asians, the association of the ADH1B*2 variant allele with drinking behaviour remains inconclusive. The goal of this study was to determine whether the polymorphic ADH1B and ALDH2 genes are associated with stroke in male Han Chinese with high alcohol consumption. Sixty-five stroke patients with a history of heavy drinking (HDS) and 83 stroke patients without such a history (NHDS) were recruited for analysis of the ADH1B and ALDH2 genotypes from the stroke registry in the Tri-Service General Hospital, Taipei, Taiwan, between January 2000 and December 2001. The allelotypes of ADH1B and ALDH2 were determined using the polymerase chain reaction-restriction fragment length polymorphism method. The HDS patients (3 per cent) showed a significantly lower ALDH2*2 allele frequency than NHDS patients (27 per cent) (p < 0.001). After controlling for age, patients with HDS were associated with a significantly higher occurrence of cigarette smoking (p < 0.01) and liver dysfunction (p < 0.01). Multiple logistic regression analyses revealed that the ALDH2*2 variant allele was an independent variable exhibiting strong protection (odds ratio 0.072; 95 per cent confidence interval 0.02-0.26) against HDS after adjustment for hypertension, diabetes mellitus, smoking status and liver dysfunction. By contrast, allelic variations in ADH1B exerted no significant effect on HDS. The present study indicated that, unlike ALDH2*2, ADH1B*2 appears not to be a significant negative risk factor for high alcohol consumption in male Han Chinese with stroke.

Keywords

alcohol dehydrogenase aldehyde dehydrogenase Han Chinese stroke high alcohol consumption allelic variation

Introduction

Stroke is the third leading cause of death and the major cause of disability requiring long-term institutionalisation in Taiwan [1]. Epidemiological evidence has shown that heavy drinking is a major risk factor for all stroke subtypes [2].

Alcohol metabolism is one of the biological determinants that can significantly influence drinking behaviour and the development of alcoholism and alcohol-related organ damage [3, 4]. Most ethanol elimination occurs via oxidation to acetaldehyde and acetate, catalysed principally by alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH), respectively [5]. The genes encoding both enzymes exhibit polymorphism and ethnic variations [6, 7]. The allelic variant ALDH2*2 is best known for its role in ethanol metabolism and has been shown to be protective against the development of alcohol dependence [8, 9]. Although the ADH1B*2 variant has also been documented as a negative risk factor for developing alcoholism, studies of its effect on drinking behaviour in Asian populations have been inconclusive [1012]. Among East Asians, including Han Chinese, Japanese and Koreans, 80-90 per cent of individuals carry the variant allele ADH1B*2: this encodes the high-activity ADH1B allozyme which catalyses the oxidation of ethanol to acetaldehyde [4, 13]. ADH1B*2 occurs with a much lower frequency in Caucasian and black populations [8]. The variant ALDH2*2 allele encodes the very-low-activity allozyme of ALDH2, impairing the conversion of acetaldehyde to acetate [4]. This inborn error of acetaldehyde metabolism occurs uniquely in about half of East Asians but is rarely seen in other ethnic groups [14].

The ALDH2*2 variant has been reported to be involved in alcohol-related diseases, including oropharyngolaryngeal, oesophageal and stomach cancer,[15] colorectal cancer,[16] breast cancer,[17] asthma[18] and myocardial infarction [19, 20]. Recently, the ALDH2 polymorphism has been found to contribute to variations in the efficacy of nitroglycerin treatment for angina and heart failure [21, 22]. Epidemiological studies indicate that heavy alcohol consumption may increase the risk of stroke;[2327] however, the potential association of allelic variations of ADH1B and ALDH2 with stroke in relation to high alcohol consumption has never been documented. The present study was undertaken to evaluate the influence of functional polymorphisms of ADH1B and ALDH2 in stroke patients with a history of heavy drinking.

Materials and methods

Demographic and clinical data

Study subjects were drawn from the patient data base for a previous case-control study conducted by one of the authors (G.-S.P.) between January 2000 and December 2001 at the Tri-Service General Hospital, Taipei, Taiwan [25]. A total of 524 male stroke patients with their first ever acute stroke had been recruited in the previous study and they all met the World Health Organization's stratified criteria for stroke. Patients with a history of previous stroke, head trauma, brain stroke precipitated during surgery or angiography, receiving therapeutic anticoagulation or antiplatelet therapy, with a bleeding diathesis, a history of illicit drug use, or concomitant serious medical illness such as malignancy, uraemia, cirrhosis of the liver, sepsis, meningoencephalitis, autoimmune disorders, vasculitides, evidence of cerebral vascular malformation or symptoms of a transient ischaemic attack were excluded. All of the recruited stroke patients received examinations including a head computed tomography (CT) scan, blood pressure measurement, an electrocardiogram (ECG), a chest X-ray, a complete blood cell count, prothrombin time (PT), partial thromboplastin time (PTT) and serum electrolyte determinations and a blood biochemistry analysis. The head CT scan was performed to differentiate haemorrhagic stroke (which has two subtypes: intracerebral haemorrhage [ICH] and subarachnoid haemorrhage [SAH]) from ischaemic stroke. Stroke outcome was measured using a modified Rankin scale at discharge. Potential risk factors for stroke were recorded by interviews, clinical examinations and laboratory tests. Diabetes mellitus (DM) was defined as patients having a fasting glucose level of 140 mg/dl or higher, or a non-fasting glucose level of 200 mg/dl or higher, or currently taking medication for DM. Hypertension was defined as patients having a systolic blood pressure greater than 140 mmHg, a diastolic blood pressure greater than 90 mmHg, or currently receiving treatment for hypertension. Hypercholesterolaemia was defined as patients having a fasting total serum cholesterol level greater than 200 mg/dl or currently receiving treatment for hypercholesterolaemia. Hypertrigly-ceridaemia was defined as patients having a fasting serum triglyceride level greater than 160 mg/dl or currently receiving treatment for hypertriglyceridaemia. Hyperuricaemia was defined as patients having a serum uric acid level greater than 8.0 mg/dl or currently taking medication for hyperuricaemia. The smoking status was recorded as cigarettes currently smoked per day. Heart disease was diagnosed from a resting ECG, echocardiography or coronary catheterisation. Liver dysfunction was defined as patients having elevated blood levels of either glutamic oxaloacetic transaminase (GOT) or glutamic pyruvic transaminase (GPT) (each greater than 40 IU/L). Stroke patients with a history of heavy drinking (HDS) were defined as having a chronic alcohol consumption of over 45 g of ethanol per day[26] or a recent mean alcohol intake exceeding 300 g of ethanol per week [27]. Stroke patients without such a history (NHDS) were characterised as not having a history of regular alcohol consumption of over 45 g of ethanol per day or 300 g of ethanol per week. Of the 524 male stroke patients, sixty-eight were HDS and 456 were NHDS. From this sample, sixty-five HDS and 83 NHDS were randomly recruited for the genotyping study of ADH1B and ALDH2. The experimental procedures were approved by the Institutional Review Board for Human Studies at the Tri-Service General Hospital, and informed consent was obtained from each patient, after the nature and possible consequences of participation in the study had been explained.

Genotyping

DNA was extracted from leukocytes, and the allelo-types of ADH1B and ALDH2 were determined using polymerase chain reaction (PCR)-restriction fragment length polymorphism (RFLP) as described previously [28].

Statistical analysis

The categorical variables were compared using the Pearson chi-square test. Continuous variables, which are expressed as mean ± standard deviation, were compared using Student's unpaired t test. The odds ratio (OR) and 95 per cent confidence interval (CI) after adjustment for confounding variables were evaluated by multiple logistic regression analysis. The statistical analyses were performed using the SAS version 9.1 statistical programs (SAS Institute Inc., Cary, NC, USA).

Results

A total of 148 men with a history of stroke were recruited into the study. The study group consisted of 65 HDS men, aged 31 to 83 years, and the control group consisted of 83 NHDS men, aged 34 to 85 years. The daily alcohol consumption in the HDS group was estimated to be 119 ± 59 g prior to the stroke. The average daily alcohol consumption in the NHDS group was negligible, since most of the men in this group drank rarely or only occasionally.

The clinical characteristics of patients are shown in Table 1. The mean age of stroke onset was significantly younger in the HDS group (58 ± 14 years) compared with the NHDS group (63 ± 12 years) (p < 0.05). With further stratification of genotypes ADH1B or ALDH2, the onset ages showed no significant difference between the HDS and NHDS groups (ALDH2*2/*2 homozygotes were excluded from the comparison, as no such genotype was found in the HDS group). Twenty-seven (41.5 per cent) of 65 HDS patients and 22 (26.5 per cent) of 83 NHDS patients were haemorrhagic. The occurrence of haemorrhagic stroke in HDS patients was marginally statistically higher than that in the NHDS patients (p = 0.058). Since heavy drinking was found to be a common risk factor for stroke in the ICH and SAH subtypes,[2933] both subtypes were included in the analysis. Only a very small number of SAH cases were found in the stroke patients (none in HDS and four in NHDS). No significant differences were found in blood pressure or in the modified Rankin scale between the HDS and NHDS groups.
Table 1

Clinical characteristics of patients with HDS and NHDS

Characteristic

NHDS

(n= 83)

HDS

(n= 65)

pvalue

Age, years

63 ± 12

58 ± 14

0.020

SBP, mmHg

154 ± 32

151 ± 30

0.477

DBP, mmHg

85 ± 20

88 ± 16

0.282

Stroke type

  

0.058

   Infarction

61 (73.5)

38 (58.5)

 

   Haemorrhage

22 (26.5)

27 (41.5)

 

MRS

  

0.230

   1

7 (8.4)

14 (21.5)

 

   2

23 (27.7)

15 (23.1)

 

   3

24 (28.9)

16 (24.6)

 

   4

15 (18.1)

12 (18.5)

 

   5

9 (10.8)

3 (4.6)

 

   6

5 (6.1)

5 (7.7)

 

Figures in parentheses are percentages. Statistical comparison was evaluated by the chi-square test. Values for age and blood pressure are expressed as mean ± SD

Abbreviations: DBP, diastolic blood pressure; MRS, modified Rankin scale; SBP, systolic blood pressure.

The relative numbers of patients with hypertension (p < 0.05) and DM (p < 0.01) were significantly lower in the HDS group than in the NHDS group, but the relative numbers of current smokers (p < 0.001) and those with liver dysfunction (p < 0.001) were significantly higher in the HDS group. After adjustment for age (Table 2), only the numbers of current smokers (p < 0.01) and those with liver dysfunction (p < 0.01) remained significantly higher in the HDS patients than in the NHDS patients. Laboratory blood test data revealed that only the serum GOT level in HDS patients was significantly higher than that in NHDS patients (p < 0.05). There was no significant difference in GPT, PT and platelet counts between the HDS and NHDS groups.
Table 2

Age-adjusted risk factors and laboratory data for HDS patients

Variables

NHDS

(n= 83)

HDS

(n= 65)

pvalue

OR

95% CI

Risk factors

No. (%)

No. (%)

   

Hypertension

63 (75.9)

38 (58.5)

0.122

0.517

0.23-1.19

Diabetes mellitus

25 (30.1)

8 (12.3)

0.300

0.590

0.22-1.60

Smoking

37 (44.6)

47 (72.3)

0.004

3.269

1.45-7.36

Hypercholesterolaemia

24 (28.9)

14 (21.5)

0.330

0.617

0.23-1.63

Hypertriglyceridaemia

20 (24.1)

10 (15.4)

0.216

0.520

0.19-1.47

Heart disease

13 (15.7)

9 (13.8)

0.688

1.251

0.42-3.73

Hyperuricaemia

12 (14.4)

14 (21.5)

0.369

1.643

0.56-4.85

Liver dysfunction

3 (4.6)

17 (26.1)

0.003

7.552

1.95-29.2

Laboratory data means ± SD

    

TG, mmol/L

155.2 ± 84.5

160.5 ± 93.3

0.830

0.999

0.99-1.01

TC, mmol/L

187.9 ± 46.3

177.0 ± 45.7

0.577

0.997

0.99-1.09

GOT, U/L

23.7 ± 10.7

71.4 ± 174.7

0.039

1.044

1.00-1.09

GPT, U/L

22.0 ± 15.4

44.0 ± 75.0

0.096

0.961

0.92-1.01

PT, s

11.3 ± 0.57

11.8 ± 1.5

0.970

1.013

0.53-1.95

PTT, s

25.8 ± 3.9

28.0 ± 5.0

0.355

1.052

0.95-1.17

PLT,/μl

220487 ± 69370

197721 ± 77945

0.148

1.000

1.00-1.00

Figures in parentheses are percentages. Statistical comparison was evaluated by the multiple logistic regression analysis. Values for laboratory data are expressed as mean ± SD

Abbreviations: PLT, platelet; TC, total cholesterol; TG, triglyceride.

Both the genotype (p < 0.001) and allele frequencies (p < 0.001) of ALDH2 in the HDS group were significantly different from those in NHDS group (Table 3). The frequencies of ADH1B genotypes and alleles were, however, similar in the two groups. Multiple logistic regression analyses showed that the ALDH2*1/*2 genotype was an independent variable with strong protection (OR 0.030; 95 per cent CI 0.002-0.396; p < 0.0078) against high alcohol consumption in stroke patients (Table 4) after adjustment for hypertension, DM, smoking status, liver dysfunction and ADH1B genotype. By contrast, allelic variations of ADH1B exerted no significant effect on the risk of heavy drinking in stroke patients by logistic regression analysis. ADH1B and ALDH2 also showed no significant interaction in the risk for heavy drinking in stroke patients (Table 4).
Table 3

Genotype and allele distribution of ADH1B and ALDH2 in patients with HDS and NHDS

Gene

N

Genotype number (frequency)

Allele number (frequency)

  

*1/*1

*1/*2

*2/*2

pValue

*1

*2

pValue

ADH1B

        

   NHDS

83

10 (0.12)

38 (0.46)

35 (0.42)

 

58 (0.35)

108 (0.65)

 

   HDS

65

9 (0.14)

26 (0.40)

30 (0.46)

0.78

44 (0.34)

86 (0.66)

0.84

ALDH2

        

   NHDS

83

45 (0.54)

31 (0.37)

7 (0.08)

 

121 (0.73)

45 (0.27)

 

   HDS

65

61 (0.94)

4 (0.06)

0 (0.00)

< 0.001

126 (0.97)

4 (0.03)

< 0.001

The statistical comparison was evaluated by the Pearson chi-square test

Table 4

Risk of functional polymorphisms of ADH1B and ALDH2 for HDS

Variable

Regression

coefficient

Standard

error

pvalue

Odds

ratio

95%

confidence

interval

ADH1B*1/*2

-0.4196

0.69

0.5428

0.66

0.170-2.539

ADH1B*2/*2

-0.2972

0.70

0.6725

0.74

0.187-2.947

ALDH2*1/*2

-3.5167

1.32

0.0078

0.030

0.002-0.396

ADH1B × ALDH2

0.7031

0.8658

0.4167

  

Constant

1.2854

0.7012

0.0668

  

HDS (n = 65); NHDS (n = 83). Statistical comparison was evaluated by multiple logistic regression after adjustment for hypertension, DM, smoking and liver dysfunction and the rest of the genotypes of ADH1B and ALDH2. The ALDH2*2/*2 genotype was not included for comparison, as no such genotype was found in the HDS group. Reference groups for ADH1B and ALDH2 were ADH1B*1/*1 and ALDH2*1/*1, respectively

Discussion

The present study revealed a significant difference in ALDH2 genotypes between the HDS and NHDS groups. The allele frequencies of ALDH2*2 were significantly lower in the HDS group (3 per cent) than in the NHDS group (27 per cent). The variant allele frequency in the HDS group was not significantly different (p = 0.056) from that found in the previous study of Han Chinese alcohol-dependent patients (8 per cent for ALDH2*2) [28]. Moreover, the frequency in the NHDS group was also similar (p = 0.421) to that in their healthy control group (24 per cent for ALDH2*2) [28]. Unexpectedly, the allelic variations of ADH1B showed similar frequencies in the two study groups. The allele frequencies of ADH1B*2 in the HDS (66 per cent) and NHDS (65 per cent) groups appeared lower (p = 0.027) than that in the non-alcoholic group of Han Chinese (73 per cent)[28] but significantly higher (p < 0.001) than that in the alcoholic group (46 per cent) [28]. This might be due, in part, to the HDS group in the present study being subject to alcohol abuse or alcohol dependence rather than to alcohol dependence alone, and in part due to the involvement of stroke with alcoholism. The results suggest that the additional disease factors associated with stroke may influence the association between ADH1B polymorphism and high alcohol consumption. Recently, it was reported that ADH1B*2 was not related to drinking behaviour in East Asians[1012] and that the variant allele showed no protective effects against alcoholism in antisocial alcoholics among Han Chinese in Taiwan [34]. It is worth noting that, unlike the ALDH2*2 variant allele,[9] the physiological basis of protection by the ADH1B*2 variant allele against developing alcohol dependence has not been resolved [8, 25].

The identification of risk factors for stroke, awareness of the relative contribution of these factors and knowledge of the interactions between them are essential for stroke prevention. The present study revealed that, without adjustment for age, the frequencies of hypertension and DM were significantly lower in the HDS than the NHDS group, and those of current cigarette smoking and liver dysfunction were significantly higher in the HDS than in the NHDS group. After controlling for age, only smoking status and liver dysfunction remained significantly different between the two groups (Table 2). Heavy alcohol consumption has been reported to be associated with cigarette smoking and to be a positive risk factor for liver dysfunction and stroke [2325, 35].

Alcoholism is a pharmacogenetic behavioural disorder involving complex gene-gene and gene-environment interactions [36]. Current evidence indicates that metabolic gene alleles ALDH2*2 and ADH1B*2 may independently influence the risk of alcoholism in Han Chinese and Koreans [28, 37]. To date, the ALDH2*2 variant allele has been shown to be the strongest genetic modifier of drinking behaviour and risk of alcoholism [28, 37, 38]. Previous genotype-phenotype correlation studies have demonstrated that non-alcoholic Asian individuals carrying the ALDH2*2 variant allele, regardless of their ADH1B genotype, responded to low-to-moderate doses of alcohol with markedly increased acetaldehyde levels, pronounced cardiovascular haemodynamic effects and unpleasant subjective feelings [25, 3941]. These adverse reactions to acetaldehyde may considerably reduce the frequency and quantity of alcohol consumption,[41, 42] thereby providing protection against excessive drinking and the development of alcoholism [39, 43]. More recent studies have indicated that physiological tolerance or an innate low response to the alcohol sensitivity reaction may contribute to the development of alcoholism in heterozygous ALDH2*1/*2 alcohol-dependent patients [44]. Notably, homozygous ADH1B*2/*2 individuals who carry the normal ADLH2*1/*1 genotype did not exhibit blood acetaldehyde accumulation after ingestion of alcohol or show alcohol flush reactions or experience unpleasant subjective perceptions [40, 43]. Logistic regression analyses of the combinatorial genotypes of ADH1B and ALDH2 in Han Chinese[8, 28] and Koreans[37] indicate that the allelic variations of these two genes may independently influence the risk of alcoholism. These observations imply that ADH1B and ALDH2 might have different target substrates or distinct target organs in affecting drinking behaviour and alcoholism. Interestingly, the ADH1B*1 allele frequency in NHDS subjects in the present study was significantly higher (p < 0.05) than that in non-alcoholic healthy controls in the previous study [28]. This is consistent with a prospective Japanese cohort study which found that the normal ADH1B*1 allele was associated with an increased risk of cerebral infarction and lacunae after adjustment for alcohol consumption [45]. Thus, it seems that the ADH1B genotype may be involved not only in ethanol metabolism, but also in some unknown biological function which influences the occurrence of stroke. Further studies, with larger samples of both HDS and NHDS subjects, are required to confirm the observations of the current study.

Conclusion

The heterozygous ALDH2*1/*2 genotype is a negative risk factor for high alcohol consumption with stroke, while smoking and liver dysfunction are positive risk factors. By contrast, ADH1B genotypes appear to have no influence on heavy drinking with stroke.

Declarations

Acknowledgements

This work was supported by grants from the National Science Council (NSC90-2314-B-016-079; NSC91-2314-B-016-063) and the Tri-Service General Hospital (TSGH-C90-50; TSGH-C98-11-S01-04).

Authors’ Affiliations

(1)
Department of Surgery, Cathay General Hospital
(2)
Department of Neurology, Tri-Service General Hospital
(3)
Department of Biochemistry and Molecular Genetics, University of Alabama
(4)
Healthcare Business Division, InfoExplorer Co., Ltd
(5)
Department of Psychiatry, Tri-Service General Hospital
(6)
Department of Biochemistry, National Defense Medical Center

References

  1. Department of Health: National Health Statistics Report, Taipei Executive. 2008Google Scholar
  2. Reynolds K, Lewis B, Nolen JD, Kinney GL, et al: Alcohol consumption and risk of stroke: A meta-analysis. JAMA. 2003, 2 (289): 579-588.View ArticleGoogle Scholar
  3. Agarwal DP, Goedde HW: Pharmacogenetics of alcohol metabolism and alcoholism. Pharmacogenetics. 1992, 2: 48-62. 10.1097/00008571-199204000-00002.View ArticlePubMedGoogle Scholar
  4. Yin SJ, Agarwal DP: Functional polymorphism of alcohol and aldehyde dehydrogenase: Alcohol metabolism, alcoholism, and alcohol-induced organ damage. Alcohol in Health and Disease. Edited by: Agarwal DP, Seitz HK. 2001, Marcel Dekker, New York, NY, 1-26.View ArticleGoogle Scholar
  5. Bosron WF, Li TK: Genetic polymorphism of human liver alcohol and aldehyde dehydrogenases, and their relationship to alcohol metabolism and alcoholism. Hepatology. 1986, 6: 502-510. 10.1002/hep.1840060330.View ArticlePubMedGoogle Scholar
  6. Smith M: Genetics of human alcohol and aldehyde dehydrogenases. Adv Hum Genet. 1986, 15: 249-290.PubMedGoogle Scholar
  7. Yoshida A, Hsu LC, Yasunami M: Genetics of human alcohol-metabolizing enzymes. Prog Nucleic Acid Res Mol Biol. 1991, 40: 255-287.View ArticlePubMedGoogle Scholar
  8. Chen YC, Peng GS, Wang MF, Tsao TP, et al: Polymorphism of ethanol-metabolism genes and alcoholism: Correlation of allelic variations with the pharmacokinetic and pharmacodynamic consequences. Chem Biol Interact. 2009, 178: 2-7. 10.1016/j.cbi.2008.10.029.View ArticlePubMedGoogle Scholar
  9. Peng GS, Yin SJ: Effect of the allelic variants of aldehyde dehydrogenase ALDH2*2 and alcohol dehydrogenase ADH1B*2 on blood acetaldehyde concentrations. Hum Genomics. 2009, 3: 121-127.PubMed CentralView ArticlePubMedGoogle Scholar
  10. Hendershot CS, Collins SE, George WH, Wall TL, et al: Associations of ALDH2 and ADH1B genotypes with alcohol-related phenotypes in Asian young adults. Alcohol Clin Exp Res. 2009, 33: 839-847. 10.1111/j.1530-0277.2009.00903.x.PubMed CentralView ArticlePubMedGoogle Scholar
  11. Takeshita T, Mao XQ, Morimoto K: The contribution of polymorphism in the alcohol dehydrogenase beta subunit to alcohol sensitivity in a Japanese population. Hum Genet. 1996, 97: 409-413. 10.1007/BF02267057.View ArticlePubMedGoogle Scholar
  12. Higuchi S, Matsushita S, Muramatsu T, Murayama M, et al: Alcohol and aldehyde dehydrogenase genotypes and drinking behavior in Japanese. Alcohol Clin Exp Res. 1996, 20: 493-497. 10.1111/j.1530-0277.1996.tb01080.x.View ArticlePubMedGoogle Scholar
  13. Lee SL, Chau GY, Yao CT, Wu CW, et al: Functional assessment of human alcohol dehydrogenase family in ethanol metabolism: Significance of first-pass metabolism. Alcohol Clin Exp Res. 2006, 30: 1132-1142. 10.1111/j.1530-0277.2006.00139.x.View ArticlePubMedGoogle Scholar
  14. Li H, Borinskaya S, Yoshimura K, Kolina N, et al: Refined geographic distribution of the oriental ALDH2*504lys (nee 487lys) variant. Ann Hum Genet. 2009, 73: 335-345. 10.1111/j.1469-1809.2009.00517.x.PubMed CentralView ArticlePubMedGoogle Scholar
  15. Yokoyama A, Muramatsu T, Omori T, Yokoyama T, et al: Alcohol and aldehyde dehydrogenase gene polymorphisms and oropharyngolaryngeal, esophageal and stomach cancers in Japanese alcoholics. Carcinogenesis. 2001, 22: 433-439. 10.1093/carcin/22.3.433.View ArticlePubMedGoogle Scholar
  16. Gao CM, Takezaki T, Wu JZ, Zhang XH, et al: Polymorphisms of alcohol dehydrogenase 2 and aldehyde dehydrogenase 2 and colorectal cancer risk in Chinese males. World J Gastroenterol. 2008, 14: 5078-5083. 10.3748/wjg.14.5078.PubMed CentralView ArticlePubMedGoogle Scholar
  17. Kawase T, Matsuo K, Hiraki A, Suzuki T, et al: Interaction of the effects of alcohol drinking and polymorphisms in alcohol-metabolizing enzymes on the risk of female breast cancer in Japan. J Epidemiol. 2009, 19: 244-250. 10.2188/jea.JE20081035.PubMed CentralView ArticlePubMedGoogle Scholar
  18. Takao A, Shimoda T, Kohno S, Asai S, et al: Correlation between alcohol-induced asthma and acetaldehyde dehydrogenase-2 genotype. J Allergy Clin Immunol. 1998, 101: 576-580. 10.1016/S0091-6749(98)70162-9.View ArticlePubMedGoogle Scholar
  19. Takagi S, Iwai N, Yamauchi R, Kojima S, et al: Aldehyde dehydrogenase 2 gene is a risk factor for myocardial infarction in Japanese men. Hypertens Res. 2002, 25: 677-681. 10.1291/hypres.25.677.View ArticlePubMedGoogle Scholar
  20. Jo SA, Kim EK, Park MH, Han C, 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. 10.1016/j.cca.2007.03.016.View ArticlePubMedGoogle Scholar
  21. Chen Z, Zhang J, Stamler JS: Identification of the enzymatic mechanism of nitroglycerin bioactivation. Proc Natl Acad Sci USA. 2002, 99: 8306-8311. 10.1073/pnas.122225199.PubMed CentralView ArticlePubMedGoogle Scholar
  22. Li Y, Zhang D, Jin W, Shao C, et al: Mitochondrial aldehyde dehydrogenase-2 (ALDH2) glu504lys polymorphism contributes to the variation in efficacy of sublingual nitroglycerin. J Clin Invest. 2006, 116: 506-511. 10.1172/JCI26564.PubMed CentralView ArticlePubMedGoogle Scholar
  23. Ikehara S, Iso H, Yamagishi K, Yamamoto S, et al: Alcohol consumption, social support, and risk of stroke and coronary heart disease among Japanese men: The JPHC study. Alcohol Clin Exp Res. 2009, 33: 1025-1032. 10.1111/j.1530-0277.2009.00923.x.View ArticlePubMedGoogle Scholar
  24. Reims HM, Kjeldsen SE, Brady WE, Dahlof B, et al: Alcohol consumption and cardiovascular risk in hypertensives with left ventricular hypertrophy: The LIFE study. J Hum Hypertens. 2004, 18: 381-389. 10.1038/sj.jhh.1001731.View ArticlePubMedGoogle Scholar
  25. Peng GS, Yin SJ, Cheng CA, Chiu SW, et al: Increased risk of cerebral hemorrhage in Chinese male heavy drinkers with mild liver disorder. Cerebrovasc Dis. 2007, 23: 309-314. 10.1159/000098445.View ArticlePubMedGoogle Scholar
  26. Wannamethee SG, Shaper AG: Patterns of alcohol intake and risk of stroke in middle-aged British men. Stroke. 1996, 27: 1033-1039. 10.1161/01.STR.27.6.1033.View ArticlePubMedGoogle Scholar
  27. Hillbom M, Numminen H, Juvela S: Recent heavy drinking of alcohol and embolic stroke. Stroke. 1999, 30: 2307-2312. 10.1161/01.STR.30.11.2307.View ArticlePubMedGoogle Scholar
  28. Chen CC, Lu RB, Chen YC, Wang MF, et al: Interaction between the functional polymorphisms of the alcohol-metabolism genes in protection against alcoholism. Am J Hum Genet. 1999, 65: 795-807. 10.1086/302540.PubMed CentralView ArticlePubMedGoogle Scholar
  29. Longstreth WT, Nelson LM, Koepsell TD, van Belle G, et al: Cigarette smoking, alcohol use, and subarachnoid hemorrhage. Stroke. 1992, 23: 1242-1249. 10.1161/01.STR.23.9.1242.View ArticlePubMedGoogle Scholar
  30. Juvela S, Hillbom M, Numminen H, Koskinen P: Cigarette smoking and alcohol consumption as risk factors for aneurysmal subarachnoid hemorrhage. Stroke. 1993, 24: 639-646. 10.1161/01.STR.24.5.639.View ArticlePubMedGoogle Scholar
  31. Juvela S, Hillbom M, Palomaki H: Risk factors for spontaneous intracerebral hemorrhage. Stroke. 1995, 26: 1558-1564. 10.1161/01.STR.26.9.1558.View ArticlePubMedGoogle Scholar
  32. Monforte R, Estruch R, Graus F, Nicolas JM, et al: High ethanol consumption as risk factor for intracerebral hemorrhage in young and middle-aged people. Stroke. 1990, 21: 1529-1532. 10.1161/01.STR.21.11.1529.View ArticlePubMedGoogle Scholar
  33. Thrift AG, Donnan GA, McNeil JJ: Heavy drinking, but not moderate or intermediate drinking, increases the risk of intracerebral hemorrhage. Epidemiology. 1999, 10: 307-312. 10.1097/00001648-199905000-00020.View ArticlePubMedGoogle Scholar
  34. Lu RB, Ko HC, Lee JF, Lin WW, et al: No alcoholism-protection effects of ADH1B*2 allele in antisocial alcoholics among Han Chinese in Taiwan. Alcohol Clin Exp Res. 2005, 29: 2101-2107. 10.1097/01.alc.0000191765.49737.55.View ArticlePubMedGoogle Scholar
  35. Bazzano LA, Gu D, Reynolds K, Wu X, et al: Alcohol consumption and risk for stroke among Chinese men. Ann Neurol. 2007, 62: 569-578. 10.1002/ana.21194.View ArticlePubMedGoogle Scholar
  36. Li TK: Pharmacogenetics of responses to alcohol and genes that influence alcohol drinking. J Stud Alcohol. 2000, 61: 5-12.View ArticlePubMedGoogle Scholar
  37. Kim DJ, Choi IG, Park BL, Lee BC, et al: Major genetic components underlying alcoholism in Korean population. Hum Mol Genet. 2008, 17: 854-858.View ArticlePubMedGoogle Scholar
  38. Higuchi S, Matsushita S, Imazeki H, Kinoshita T, et al: Aldehyde dehydrogenase genotypes in Japanese alcoholics. Lancet. 1994, 343: 741-742.View ArticlePubMedGoogle Scholar
  39. Peng GS, Wang MF, Chen CY, Luu SU, et al: Involvement of acetaldehyde for full protection against alcoholism by homozygosity of the variant allele of mitochondrial aldehyde dehydrogenase gene in Asians. Pharmacogenetics. 1999, 9: 463-476.PubMedGoogle Scholar
  40. Peng GS, Yin JH, Wang MF, Lee JT, et al: Alcohol sensitivity in Taiwanese men with different alcohol and aldehyde dehydrogenase genotypes. J Formos Med Assoc. 2002, 101: 769-774.PubMedGoogle Scholar
  41. 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. 10.1111/j.1530-0277.1999.tb04226.x.View ArticlePubMedGoogle Scholar
  42. Sun F, Tsuritani I, Yamada Y: Contribution of genetic polymorphisms in ethanol-metabolizing enzymes to problem drinking behavior in middle-aged Japanese men. Behav Genet. 2002, 32: 229-236. 10.1023/A:1019711812074.View ArticlePubMedGoogle Scholar
  43. Peng GS, Chen YC, Tsao TP, Wang MF, et al: Pharmacokinetic and pharmacodynamic basis for partial protection against alcoholism in Asians, heterozygous for the variant ALDH2*2 gene allele. Pharmacogenet Genomics. 2007, 17: 845-855. 10.1097/FPC.0b013e3282609e67.View ArticlePubMedGoogle Scholar
  44. Chen YC, Peng GS, Tsao TP, Wang MF, et al: Pharmacokinetic and pharmacodynamic basis for overcoming acetaldehyde-induced adverse reaction in Asian alcoholics, heterozygous for the variant ALDH2*2 gene allele. Pharmacogenet Genomics. 2009, 19: 588-599. 10.1097/FPC.0b013e32832ecf2e.View ArticlePubMedGoogle Scholar
  45. Suzuki Y, Fujisawa M, Ando F, Niino N, et al: Alcohol dehydrogenase 2 variant is associated with cerebral infarction and lacunae. Neurology. 2004, 63: 1711-1713. 10.1212/01.WNL.0000142971.08275.DB.View ArticlePubMedGoogle Scholar

Copyright

© Henry Stewart Publications 2011