Correspondence: Prof. Jin-Sang Yoon, Department of Psychiatry, Chonnam National University Medical School, 5 Hak-dong, Dong-ku, Kwangju 501-757, Korea 
Tel: +82-62-220-6142, Fax: +82-62-225-2351, E-mail: jsyoon@chonnam.ac.kr

Introduction

The inactive form of mitochondrial aldehyde dehydrogenase (ALDH2) is encoded by heterozygous ALDH2 * 1/2 * 2 or homozygous ALDH2 * 2/2 * 2, while the active form of ALDH2 is encoded by homozygous ALDH2 * 1/2 * 1¹. The inactive form of ALDH2 is found in 20~40% of Asian populations but is rare in Caucasians^2,3,4,. It causes deficiency of ALDH2, which metabolizes acetaldehyde into acetate. Alcohol drinking in people with the inactive form of ALDH2 leads to transient hyperacetaldehydemia, which is related to adverse psychophysiological responses such as facial flushing, chest palpitation, or dysphoria⁵. These responses have a substantial inhibitory effect on alcohol consumption, and thus prevent the likelihood of alcoholism^6,7,8. However, some people with the inactive form of ALDH2 do become alcoholics. The inactive form of ALDH2 has been found in 5~9% of Asians with alcoholism^3,4,9. Some studies tried to elucidate characteristics of this particular group, i.e. that persist in drinking despite the adverse responses. A case-control study with hospitalized adult sample reported no significant differences in socio-familial backgrounds and psychopathologies between alcoholics with the inactive and the active forms of ALDH2, but onset age of habitual drinking was delayed in those with the inactive form¹⁰. It could be reasonably hypothesized that there might be differences in risk factors for alcoholism between the two groups. However to our knowledge, there has been no research to test this hypothesis. 
This study aimed to compare the clinical characteristics and risk factors for alcoholism between the inactive and the active forms of ALDH2 in a Korean elderly population. From a viewpoint of gene-environment interaction, it was hypothesized that there would be differences in risk factors (environment) between the two different groups of genetic susceptibility to alcoholism. 

Methods and Materials 

This study was part of a community survey of latelife psychiatric morbidity carried out in Kwangju, South Korea in 2001, in collaboration with the 10/66 Dementia in Developing Countries Research Program¹¹. Data were gathered using a structured questionnaire developed by the 10/66 Dementia in Developing Countries Research Group unless specified. Details of this project have been reported elsewhere¹². 

Study Population 
Potential participants for this study were recruited from all inhabitants aged 65 or over recorded in national residents registration lists within two areas (one urban, one rural) of Kwangju, South Korea in 2001. All analyses of the study were restricted to male participants for the following reasons: i) it was reported that a very low rate of alcohol drinking in women and therefore lack of statistical power to investigate associations in this group;¹³ ii) characteristics of female alcoholics differ in many aspects from those of male alcoholics¹⁴. The study was approved by Chonnam National University Hospital Review Board. After sending a letter explaining the purpose of study to all eligible older people, written informed consent was obtained from all participants. 

Assessment procedures 
This study was conducted in two phases: 1) Sixteen graduate-level research assistants, trained and supervised by the project psychiatrist, carried out home-based interviews with participants and their family members. This included alcohol related characteristics, socio-demographic and clinical characteristics, and reports of chronic medical illnesses; 2) At a second interview (attempted in all participants), clinical diagnoses of alcoholism and blood tests for ALDH2 genotypes and physical condition were administered by two expert teams, consisting of a psychiatrist, a senior nurse, and a psychologist. At both stages, home visits were repeated on at least two occasions if no contact was made. The mean (SD) interval between the two interviews was 8.7 (5.4) days. People who completed the two interviews and the blood tests formed the sample for the analysis presented here. 

Alcohol related characteristics 
These were obtained from the participants, and corroborated by their family members if possible, using a questionnaire developed by 10/66 Dementia Research Group and the alcohol-related section of the Geriatric Mental State Schedule (GMS)¹⁵. If there was disagreement between the participant and informant, information from the informant was given salience. Data on age at onset of drinking, family history of alcoholism, and previous treatment history for alcohol related problems were ascertained. Alcohol consumption was computed in terms of average weekly intake, measured in drinks (1 drink=12 grams of pure alcohol). An estimate of lifetime alcohol consumption was made by multiplying the average weekly consumption by the number of years that the subject drank in a particular pattern. Additionally, the Alcoholism Screening Test of Seoul National Mental Hospital-I (NAST-I)¹⁶ was used to evaluate symptoms of alcoholism. It is composed of 12 items, yielding a maximum score of 12. The nine items of the alcohol-related section of the GMS yields a maximum score of 13. 

Socio-demographic characteristics 
Information on age, living area (urban or rural), marital status (having spouse or not), religious observation, level of education, type of accommodation (owned or rented), past occupation (manual or non-manual), and current (post-retirement) employment was gathered. 

Chronic medical illnesses 
It was quantified by a structured questionnaire enquiring about 11 common health problems: arthritis or rheumatism; eyesight problems; hearing difficulty or deafness; persistent cough; breathlessness, difficulty breathing or asthma; high blood pressure; heart disease ORIGINAL ARTICLES 73.74 or angina; gastric or intestinal problems; faints or blackouts; paralysis, weakness or loss of power in one leg or arm; and skin disorders such as pressure sores, leg ulcers or severe burns. The questionnaire was developed for evaluating physical health in elderly¹⁷, and has been used in well-known previous studies¹⁸. These health problems were coded as present or absent and the individual scores totalled to generate a summary scale. 

Diagnoses of alcoholism 
A semi-structured questionnaire to permit DSM-IV¹⁹ diagnoses of alcohol abuse and alcohol dependence was administered by psychiatrists. Through the consensus conference, DSM-IV diagnoses of alcohol abuse and alcohol dependence were determined in conjunction with the above alcohol related data and taking into account changes in the NAST-I scores, evaluated two years earlier in 64% participants¹⁸. 

Blood tests 
Genotypes for the ALDH2 genes were determined by previously described methods²⁰ with minor modifications. Of the three ALDH2 genotypes, ALDH 2 * 1/2 * 1 was classified as 'active form of ALDH2', and ALDH2 * 1/2 * 2 or ALDH2 * 2/2 * 2 were classified as 'inactive form of ALDH2'. Additional blood tests, known to be changed sensitively to alcoholism, were measured for serum glutamic-oxaloacetic transaminase (SGOT), serum glutamic-pyruvic transaminase (SGPT), high density lipoprotein (HDL) cholesterol, and mean corpuscular volume (MCV). The results were categorized to be abnormal when SGOT>40mg/dL, SGPT>40mg/dL, HDL cholesterol<29mg/dL, and MCV>100. 

Statistical analysis 
Various characteristics in all participants were compared according to ALDH2 genotype using t-tests or chisquare tests as appropriate. The same analyses were repeated in those only with alcoholism. Univariate associations between alcoholism and independent variables were analyzed by chi-square tests. Factors potentially associated with alcoholism (p<0.05) on the univariate analyses were then entered simultaneously into a logistic regression model to investigate confounding and mediating factors with respect to the association of interest between ALDH2 genotypes and alcoholism. Statistical analyses were conducted with SPSS 12.0 software. 

Results 

Recruitment 
Of all 1566 inhabitants aged 65 or over identified from registration lists, 644 (41%) were men. Of them, 284 (44%) men participated in the study. Of the participants, 104 (37%) were diagnosed to have DSM-IV alcoholism. (37alcohol abuse; 67 alcohol dependence) With respect to ALDH2 genotypes, 205 (72%) had the active form, and 79 (28%) had the inactive form. 

Comparison according to ALDH2 genotypes in the total participants 
The total sample is described and genotypes are compared in Table 1. Participants with the active form of ALDH2 had increased alcohol related problems but did not differ from the inactive form of ALDH2 group with respect to family history of alcoholism. There were no significant group differences with respect to socio-demographic characteristics. In terms of physical health relat-ed characteristics, SGOT abnormality was significantly more frequent in the active form group, while no differences were fond in other aspects. 

Comparison according to ALDH2 genotypes in the alcoholics 
Various characteristics according to ALDH2 genotypes in those with alcoholism were compared in Table 2. There were no significant differences in any aspects between the two groups. 

Univariate associations with alcoholism 
Univariate associations with alcoholism are summarized in Table 3. Alcoholism was more prevalent in the rural sample, in those without religious observation, in those with a previous manual occupation, in the currently employed group, in those with family history of alcoholism, and in those with the active form of ALDH2. 

Multivariate associations with alcoholism 
The results of logistic regression analyses are summa rized in Table 4. Of the independent variables associated with alcoholism in the univariate analyses, the active form of ALDH2, current employment and family history of alcoholism were significant factors for alcoholism. However, these associations were apparently confined in those with the active form of ALDH2. Any variable was identified as independent risk factors for alcoholism in those with the inactive form of ALDH2. 

Discussion 

Alcoholism yields to various negative consequences in the patients and their family members. Studies on the clinical characteristics and risk factors of alcoholism are beneficial to set up the prevention and treatment strategies. Alcoholics with the inactive form of ALDH2 are very particular group, because they became alcoholics in spite of the genetic preventative factor. The authors hypothesized that they had some particular characteristics, which overcome the genetic preventative factor. 
In the total participants, those with the active form of ALDH2 had increased alcohol related problems, consistent with previous studies^6,7,8. The finding that SGOT abnormality was more common in those with the active form of ALDH2, reflected the more frequent alcohol drinking in the group. 
However in those only with alcoholics, no differences were found in any aspects between those with the active and inactive forms of ALDH2. These results were substantially overlapping with a previous Japanese study,¹⁰ while were unexpected by the authors. These could be a Type II error, caused by small numbers the alcoholics particularly in those with the inactive form of ALDH2. To clarify this issue, a larger study with more number of participants will be needed. The age at onset of alco holism was significantly delayed in those with the inac-tive form in the previous Japanese study 10 , while was not different in the present study. This discrepancy might be due to the age differences of the subjects between the two studies that mean age was 50 in the Japanese study, 72 in the present study. It could also be possible that the older age of this participants might obscure the accurate reports on the age of onset. 
In the present study, three variables were identified as independent risk factors for alcoholism: the active form of ALDH2, current employment and family history of alcoholism. Currently employed persons had money for buying alcoholic beverages and so were apt to be alcoolics^13,21. The associations of alcoholism with the active form of ALDH2 and family history of alcoholism were universal findings^6,7,8. 
The most unique findings of the present study were on the independent risk factors for alcoholism according to the ALDH2 genotypes. The results in the participants with the active form of ALDH2 were similar to those in the all participants. However in those with the inactive form of ALDH2, any variables were identified as independent risk factors for alcoholism. These results could be interpreted as below. First, persons with the inactive form of ALDH2 who drank much alcohol could have higher mortality due to the accumulated acetaldehyde for a long time. They would be missed in the survey, and therefore potential significant associations could be weakened. Second, it could be a Type II error, caused by small numbers of the alcoholics with the inactive form of ALDH2. Third, other risk factors for alcoholism such psychopathologies as depression or anxiety might be severe in those with the inactive form of ALDH2, while unfortunately these were not examined in the study. 
In summary, there were no significant differences in clinical characteristics of alcoholism between those with the active and inactive forms of ALDH2, while the risk factors of alcoholism were varied between the two groups. It could be suggested that different preventive strategies for alcoholism might be needed according to the ALDH2 polymorphism. This study has some limitations in terms of sample size and study design, but could provide grounds for future studies on this issue.

1. 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 (1): 314-6. 

2. Goedde HW, Agarwal DP, Harada S, Meier-Tackmann D, Ruofu D, Bienzle U, Kroeger A, Hussein L. Population Genetic studies on aldehyde dehydrogenase isozyme deficiency and alcohol sensitivity. Am J Hum Genet. 1983; 35 (4): 769-72. 

3. Higuchi S, Matsushita S, Imazeki H, Kinoshita T, Takagi S, Kono H. Aldehyde dehydrogenase genotypes in Japanese alco-holics. Lancet. 1994; 343 (8899): 741-2. 

4. Lee KH, Kwak BY, Kim JH, Yoo SK, Yum SK, Jeong HS. Genetic polymorphism of cytochrome P-4502E1 and mito-chondrial aldehyde dehydrogenase in a Korean population. Alcohol Clin Exp Res. 1997; 21 (6): 953-6. 

5. Goedde HW, Agarwal DP, Fritze G, Meier-Tackmann D, Singh S, Beckmann G, Bhatia K, Chen LZ, Fang B, Lisker R, Paik YK, Rothhammer F, Saha N, Segal B, Srivastava LM, Czeizel A. Distrubution of ADH2 and ALDH2 genotypes in different populations. Hum Genet. 1992; 88 (3): 344-6. 

6. Thomasson HR, Edenberg HJ, Crabb DW, Mai XL, Jerome RE, Li TK, Wang SP, Lin YT, Lu RB, Yin SJ. Alcohol and aldehyde dehydrogenase genotypes and alcoholism in Chinese men. Am J Hum Genet. 1991; 48 (4): 677-81. 

7. Higuchi S, Matsushita S, Murayama M, Takagi S, Hayashida M. Alcohol and aldehyde dehydrogenase polymorphisms and the risk for alcoholism. Am J Psychiatry. 1995; 152 (8): 1219-21. 

8. Higuchi S, Matsushita S, Muramatsu T, Murayama M, Hayashida M. Alcohol and aldehyde dehydrogenase genotypes and drinking behavior in Japanese. Alcohol Clin Exp Res. 1996; 20 (3): 493-7. 

9. Chen CC, Lu RB, Chen YC, Wang MF, Chang YC, Li TK, Yin SJ. Interaction between the functional polymorphisms of the alcohol-metabolism genes in protection against alcoholism. Am J Hum Genet. 1999; 65 (3): 795-807. 

10. Murayama M, Matsushita S, Muramatsu T, Higuchi S. Clinical characteristics and disease course of alcoholics with inactive aldehyde dehydrogenase-2. Alcohol Clin Exp Res. 1998; 22 (2): 524-7. 

11. Prince M, Acosta D, Chiu H, Scazufca M, Varghese M. 10/66 Dementia Research Group. Dementia diagnosis in developing countries: a cross-cultural validation study. Lancet. 2003; 361 (9361): 909-17. 

12. Kim JM, Stewart R, Shin IS, Jung JS, Yoon JS. Assessment of association between mitochondrial aldehyde dehydrogenase polymorphism and Alzheimer's disease in an older Korean population. Neurobiol Aging. 2004; 25 (3): 295-301. 

13. Kim JM, Shin IS, Stewart R, Yoon JS. Alcoholism in older Korean men: prevalence, aetiology, and comorbidity with cog-nitive impairment and dementia in urban and rural communi-ties. Int J Geriatr Psychiatry. 2002; 17 (9): 821-7. 

14. Gomberg ES. Recent developments in alcoholism:gender issues. Recent Dev Alcohol. 1993; 11: 95-107. 

15. Copeland JRM, Dewey ME, Griffiths-Jones HM. A computer-ized psychiatric diagnostic system and case nomenclature for elderly subjects: GMS and AGECAT. Psychol Med. 1986; 16 (1): 89-99. 

16. Kim KB, Hahn KS, Lee JK, Rhee MK, Kim YK, Kim CK. The preliminary study of the Korean Alcoholism Screening Test (III): Alcoholism Screening Test of Seoul National Mental Hospital (I) NAST (I). J Korean Neuropsychiatr Assoc. 1991; 30 (3): 569-81. 

17. Lindesay J. The Guy's/Age Concern Survey: physical health and psychiatric disorder in an urban elderly community. Int J Geriatr Psychiatry. 1990; 5: 171-8. 

18. Prince MJ, Harwood RH, Blizard RA, Thomas A, Mann AH. Impairment, disability and handicap as risk factors for depres-sion in old age. The Gospel Oak Project V. Psychol Med. 1997; 27 (2): 311-21. 

19. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorder, 4 th ed. Washington, DC, American Psychiatric Press, 1994. 

20. Takeshita T, Morimoto K, Mao X, Hashimoto T, Furuyama J. Characterization of the three genotypes of low Km aldehyde dehydrogenase in a Japanese population. Hum Genet. 1994; 94 (3): 217-23. 

21. Welte ZW, Mirand AL. Alcohol use by the elderly: Patterns and correlates. A report on the Erie County elder drinking sur-vey. Research Institute on Addictions, Buffalo, New York, 1992.