Risk Factors for Alcoholism among Taiwanese Aborigines

Risk Factors for Alcoholism among Taiwanese Aborigines Introduction Like most mental disorders, Alcoholism is a complex disease involving naturenurture interplay (1). The influence from the bio-psycho-social environment is probably life-long, and can only be investigated thoroughly via longitudinal study in the community. Recent studies have suggested that there are common genes and diseasespecific genes for alcoholism and all other drug dependence (including nicotine) (2); and that the only replicated findings are genes encoding for the alcohol metabolizing enzymes, which serve as protective influences in exposure to alcoholism (3). The active ADH2*2 allele as a protective factor for alcoholism is predominant among Asian populations including the aboriginal Taiwanese (4), and is rare among Caucasian ethnic- Table 1. Leading causes of death in four aboriginal groups and Taiwan ities (3). Although alcoholism has long 322.5 267.6 114.9 60.1 92.6 46.3 8.6 657.8 170.7 70.3 94.3 78.0 83.2 161.3 980.3 137.0 129.8 62.3 16.6 50.9 5.3 1.8 425.7 133.2 92.2 23.7 32.7 14.0 129.9 562.7 203.6 134.2 60.2 37.0 37.0 64.8 4.6 666.5 162.0 99.5 76.4 74.1 85.6 168.9 870.1 123.6 107.3 45.5 26.0 35.8 16.3 0.0 661.9 135.0 76.4 42.3 92.7 73.2 242.3 785.5 74.8 61.1 31.4 3.5 26.2 11.7 2.0 401.5 141.0 80.8 12.3 26.4 16.9 130.5 476.3 been regarded as much less severe in Han Chinese than in white populations (5), some evidence may have suggested that it has gradually become an emerging public health and social problem in the former (6). There was a 30% increase in the average per capita alcohol consumption in Taiwan from 1981- *pooled rates in 1981-85 Source: Cheng and Hsu, 1992 (9) 1985 to 1996-2000; and a high prevalence of alcoholism 46

Table 2. Abnormal liver function, alcoholism and hepatitis C infection among four aboriginal groups in Taiwan HCV infection/current % of elevated Odds Ratio+ (16.5%) was found among general medical inpatients in a recent study (5). For the Taiwanese aborigines, alcoholism has been very prevalent with serious physical, alcoholism status HCV (-)/Alcoholic (-) HCV (-)/Alcoholic (+) HCV (+)/Alcoholic (-) HCV (+)/Alcoholic (+) ALT/AST* 1.8 5.9 10.0 37.5 (95% CI) 1.0 2.4 (1.7-5.5) 5.9 (0.7-54.6) 22.6 (6.5-73.7) psychological and sociolegal complications (Tables 1 and 2) (7) (8). *Elevated ALT/AST level was defined as ALT > 35 IU/L and AST > 40 IU/L. +The odds ratios have been adjusted for the effects of both group and sex. Source: Shen et al, 1996 (8) To establish the temporal relationships between potential risk factors and alcoholism, longitudinal studies that include incidence cases of alcoholism should be considered. However, few studies have simultaneously investigated genetic and environmental risk factors for alcoholism in a single cohort hitherto. The Longitudinal study of alcoholism among Taiwanese aborigines This study was started from 1986-88 among four major aboriginal groups, the Ami, Atayal, Bunun, and Paiwan. The four groups belong to the Malayo-Polynesian stock. They can be distinguished from each other not only by geographic distribution, but also by extensive differences in physiognomy, language, and socio-cultural institutions. The extent of acculturation among them that took place rapidly in the past 30 years has differed considerably between groups and among individuals. However, there have been few inter-ethnic marriages among the groups, as well as between them and the Han Taiwanese (9). In the first cross-sectional survey among a random sample of individuals of both sexes aged 15 and above (n=993, 511 men and 482 women), high prevalence rates of alcohol use disorders were found in the four groups, ranging from 44.5 to 54.5 % (70.3% in men and 27.6% in women) (7). There were 499 sample subjects who did not have any lifetime drinking problem, and have thus formed a normal cohort. A 4-year follow-up study was conducted in 1990-92 with an overall response rate of 99.6%. The mean duration of follow-up was 4.3 (SD=0.5) years. Among the 499 normal cohort subjects, there were totally 79 incidence cases of alcoholism (15%). We found high age-standardized annual incidence rates of new alcoholic cases in the four groups, ranging from 2.8 to 4.9%, as well as high cumulative rates of alcoholism (10) (Figure 1). The cumulative rate for alcoholism was over 60% at the age of 25 in men (over 30% in women), and reached 90% at the age of 65 in men (around 70% in women). 47

Alcohol-metabolizing genes across different ethnic groups Our previous study found low frequencies (0.02 to 0.05) of the inactive allele of alcohol metabolizing enzyme aldehyde dehydrogenase gene ALDH2*2 and high frequencies (0.94 to 1.00) of the active allele of alcohol dehydrogenase gene ADH3*1 among normal controls from the four ethnic groups (4) (Table 3). The evidence indicates that neither ALDH2 nor ADH3 can be used to examine the risk for alcoholism at the individual level. However, a sizable proportion of normal cohort subjects across the four groups (0.14 to 0.30%) have the less active allele ADH2*1 acting as a genetic vulnerability factor for alcoholism among these groups. Figure 1 Cumulative risks (standard errors indicated by vertical bars, by age group) of alcoholism in the four aboriginal groups in Taiwan, 1986-1990, for men ( ) and women ( ------ ). Cumulative risk(%) 100 90 80 70 60 50 40 30 20 10 0 Risk factors for alcoholism among the normal cohort in 4-year follow up Among the 499 cohort subjects, 8 did not have complete data on sociocultural variables at the first cross-sectional survey and were excluded from the data analysis. In univariate Cox proportional hazards regression analysis, we found that there were significantly more incidence cases in young males and in those who had a family history of alcoholism in first-degree relatives. When multivariate Cox proportional hazards regression analysis was exercised, two interactions were retained in the final model, one between age and anxiety disorders, and the other between sex and ADH2 (Table 4). (11) The risk for alcoholism was highest among subjects aged 25-34 with anxiety disorders (Odds ratio, 16.86; 95% Confidence interval, 3.98 71.41), followed by subjects aged 15-24 without anxiety disorders. It was also highest among male subjects with one or two alleles of the less active ADH2*1 gene (OR, 5.87; 95% CI, 2.73-12.60), followed by men without such inheritance. This effect was however not found in females. For aboriginal subjects aged 25-34, the population attributable risk (PAR) for alcoholism due to anxiety disorders was estimated to be 31.1% (preventive fraction). For males, the PAR due to ADH2*1 alleles was estimated to be 34.7%. Male Discussion and conclusions Female Mental disorders, notably depressive disorders and anxiety disorders 25 45 65 have been speculated to be closely related to alcoholism. The nature of 48

Table 3. Allele frequencies of ADH2*2, ADH3*1 and ALDH2*2 among Taiwanese aborigines and other populations (inactive) (active) (inactive) such relationships is by Taiwanese Aborigines a no means simple and Atayal.85.95.03 straightforward. Our Ami.70 1.00.02 findings in the 4-year follow up among all of the Paiwan.86.99.05 Bunun.84.94.02 four Taiwanese aboriginal groups have lent sup- Caucasians c.04.54.00 Han Chinese b.73.95.30 port to the self-medication hypothesis regarding (All from non-alcoholic controls) a Chen et al (1997); b Thomasson et al (1991); c Gilder et al (1993) anxiety disorders, notably Source: Chen et al, 1997 (4) among young adults. Our findings suggest that depression mainly affects the course of alcoholism, including the transition from abuse to dependence, and is frequently a psychological complication of alcoholism. Although it is evident that ALDH2*2 and ADH3*1 do not have any protective effects against alcoholism among Taiwanese aborigines, the ADH2*2 allele is protective effect from the ADH2*2 among men of this ethnicity, as evident in the follow up study. Our currently ongoing 14 to18-year follow up is expected to identify more female alcoholic subjects to examine the role of ADH2*2 among the female Taiwanese aborigines, and to evaluate whether sex modifies the effect of ADH2 on the risk for alcoholism. The highest incidence and prevalence rates of alcoholism among the Bunun might have come from two potential risk factors. Genetically, a significant association between alcohol dependence and the tryptophan hydrogenase gene was only found in the Bunun, suggesting the likelihood of ethnic heterogeneity among the four groups (11). Environmentally, the Bunun were the last among the four groups to make contact with modern civilization. (7). A family history of alcoholism was observed to be a significant predictor for the occurrence of alcoholism in all groups in the 4-year follow up. However, this effect was not found in multivariate analysis. A probable explanation is that the social drinking pattern in these aboriginal communities may have diluted the effect of the family environment, and the genetic influence may have largely expressed through other biological markers including alcohol-metabolizing genes. Implications for prevention and research This study suggests that the prevention of alcoholism among these four aboriginal groups should focused on the early identification and management of anxiety disorders among subjects with a genetic vulnerability to alcohol-metabolizing enzymes and with sociocultural risk factors for alcoholism. Our results also indicate that findings from molecular genetic studies on ADH2*2 ADH3*1 ALDH2*2 49

Table 4. Joint effects of socio-cultural, psychiatric and genetic risk factors of alcoholism: Multivariate analysis using a Cox regression model adjusted for missing genotype data Relative risk (95% CI) P Age*anxiety disorder > 35 with disorder 1.00 > 35 without disorder 1.83 (0.52-6.41) 0.351 25-34 with disorder 11.46 (2.72-48.33) 0.001 25-34 without disorder 2.51 (0.70-9.00) 0.157 15-24 with disorder 4.14 (0.90-18.93) 0.067 15-24 without disorder 5.39 (1.67-17.66) 0.005 Sex*ADH2 Female, GA+GG 1.0 Female, AA 1.46 (0.65-3.25) 0.358 Male, AA 2.42 (1.13-6.48) 0.048 Male, GA+GG 5.98 (2.77-12.91) 0.001 AA: ADH2*2/*2; GA: ADH2*1/*2; GG: ADH2*1/*1 Source: Cheng et al, 2004 (11) alcoholism among severe alcoholic patients need to be verified by longitudinal studies among representative cohort subjects from the community. We expect to be able to examine the effects of gene-environment interactions on alcoholism more thoroughly with cross-ethnic comparisons when our ongoing 14 to18-year follow up in all four groups will be completed. Andrew T. A. Cheng Institute of Biomedical Sciences, Academia Sinica Arch Gen Psychiatry 61, 184-191 (2004) References 1. Heath, A.C. et al. Gene-environment interaction effects on behavioral variation and risk of complex disorders: the example of alcoholism and other psychiatric disorders. Twin Res. 5, 30-37 (2002). 2. Tsuang, M.T. et al. Co-occurrence of abuse of different drugs in men: The role of drug-specific and shared vulnerabilities. Arch Gen Psychiat. 55, 967-972 (1998). 3. Long, J.C. et al. Evidence for genetic linkage to alcohol dependence onchromosomes 4 and 11 from an autosome-wide scan in an American Indian population. Am J Med Genet. 81, 216-221 (1998). 4. Chen, W.J. et al. Alcohol dehydrogenase and aldehyde dehydrogenase genotypes and alcoholism among Taiwanese aborigines. Biol Psychiat. 41, 703-709 (1997). 5. Singer, K. Drinking pattern and alcoholism in the Chinese. Br J Addict, 67, 3-14 (1972). 6. Chen, C.H. et al. Prevalence and identification of alcohol use disorders among non-psychiatric inpatients in one general hospital. Gen Hosp Psychiat. 26, 219-225 (2004). 7. Cheng, A.T. & Chen, W.J. Alcoholism among four aboriginal groups in Taiwan: high prevalences and their implications. Alcohol Clin Exp Res. 19, 81-91 (1995). 8. Shen, C.Y. et al. Alcoholism, hepatitis B and C viral infections, and impaired liver function among Taiwanese aboriginal groups. Am J Epidemiol. 143, 936-942 (1996) 9. Cheng, T.A. & Hsu, M. A community study of mental disorders among four aboriginal groups in Taiwan. Psychol Med. 22, 255-263 (1992) 10. Chen, W.J. & Cheng, A.T.A. Incidence of first onset alcoholism among Taiwanese aborigines. Psychol Med. 27, 1363-71 (1997) 11. Cheng, A.T.A. et al. A 4-year longitudinal study on risk factors for alcoholism. Arch Gen Psychiat. 61, 184-191 (2004) 12. Sun, H.S. et al. A functional polymorphism in the promoter region of the tryptophan hydroxylase gene is associated with alcohol dependence in one aboriginal group in Taiwan. Alcohol Clin Exp Res. 29, 1-7 (2005). 50