1. ALDH2 and Conduct Disorder Mediate Ethnicity and Alcohol Dependence in Chinese-, Korean-, and White-American College Students S.E. Luczak, T.A.R. Cook, S.H. Shea, L.G. Carr, & T.L. Wall University of California, San Diego and Veterans Medical Research Foundation  Previous studies find Asians, as a group, have lower rates of alcohol dependence than Whites. Within Asians, however, Koreans have high rates while Chinese have much lower rates of alcohol dependence.  Different rates of alcohol dependence might be explained by differences in the prevalence of aldehyde dehydrogenase ALDH2*2 and alcohol dehydrogenase ADH2*2 alleles. These alleles are prevalent among Asians but rare in Whites, and are associated with protection from alcohol dependence.  As hypothesized, ALDH2 status and conduct disorder mediated the relationship between ethnicity and alcohol dependence, and gender did not seem to further influence this association.  It appears that it is differences in the prevalence rates of ALDH2 status and conduct disorder across ethnic groups and gender, rather than differences in the influences of these variables in each subgroup, that account, in part, for different rates of alcohol dependence in Chinese, Korean, and White Americans.  Being Chinese remained a significant protective factor for alcohol dependence. What affords Chinese additional protection remains to be determined.  Limitations to the study include the use of self- report measures collected at one time point, a volunteer sample, and a restricted age range. Participants  604 college students (50% women) 21 - 26 years of age (22.0 ± 1.26) of Chinese (n = 190), Korean (n = 214), and White (n = 200) heritage. Data Collection  A blood sample from each participant was genotyped at the ALDH2 and ADH2 loci.  The SSAGA was used to diagnose participants for lifetime histories of conduct disorder and alcohol dependence, including ages of onset. Data Analysis  Univariate logistic regressions were conducted to determine the significance of each predictor variable to a lifetime diagnosis of alcohol dependence.  The hypothesized mediation model was tested using the guidelines by Baron and Kenny (1986). Step   and Odds Ratios for Alcohol Dependence _____________________________________________________________ Step   (p) OR (p) _____________________________________________________________ ALDH2*2(+)13.2 (.000) 0.29 (.001) ADH2*2(+) 4.8 (.029)0.57 (.028) Conduct Disorder32.6 (.000)1.59 (.000) Male12.4 (.000)2.53 (.001) Ethnicity16.2 (.000) White1.0 (fixed) Chinese0.24 (.000) Korean0.71 (.210) Method Introduction Discussion Results Acknowledgements This research was funded by NIH Grants: K02 AA00269, R01 AA11257, P50 AA07611, and M01 RR00827, P60 AA06420, F31 AA05546, T32 AA13525, and a grant from the Alcoholic Beverage Medical Research Foundation. _____________________________________________________________________________________________________________________________________ Primary Pathway of Alcohol Metabolism _____________________________________________________________________________________________________________________________________ ALCOHOL ACETALDEHYDE ACETATE Alcohol Dehydrogenase Aldehyde Dehydrogenase Alcohol Dehydrogenase Aldehyde Dehydrogenase_________________________________________________________________ Polymorphic Genes ADH2*1 ALDH2*1 ADH2*2 ALDH2*2 ADH2*2 ALDH2*2 ADH2*3 ADH2*3 ADH3*1 ADH3*1 ADH3*2 ADH3*2_________________________________________________________________ Conduct Disorder Alcohol Dependence ADH2*2(+) ALDH2*2(+) Step 3 of Mediation Test of Alcohol Dependence _____________________________________________________________ Step   p _____________________________________________________________ 1. ALDH2*2(+)13.2.000 2. Conduct Disorder34.7.000 3. Ethnicity 5.8.055 3a. White 3.2.074 3b. Chinese 4.8.029 3c. Korean 0.0.961 16.4 (.000) 5.8 (.055) 5.8 (.055) 13.2 (.000) 31.7 (.000) 34.7 (.000) Alcohol Dependence Ethnicity (Chinese, Korean, White) Korean, White) Conduct Disorder ALDH2*2(+)  Another factor that has been consistently and strongly associated with alcohol dependence in both men and women is conduct disorder. Rates of conduct disorder across Asians and Whites are not known, but rates of the more severe antisocial personality disorder have been shown to differ across these ethnic subgroups.  Based on previous research, we hypothesized ALDH2*2 and ADH2*2 alleles to be protective factors and conduct disorder to be a risk factor for alcohol dependence, with similar relationships expected across ethnicity and gender.  We further hypothesized that it would be the differences in the prevalence rates of these vulnerability factors that result in different rates of alcohol dependence across these ethnic subgroups. Final Mediation Model  ALDH2 and ADH2 status did not differ across gender, but did differ across ethnicity,  2 (2, N = 604) = 135.05, p =.000 and  2 (2, N = 604) = 421.39, p =.000, respectively.  More Chinese (52%) possessed an ALDH2*2 allele than Koreans (34%), and no Whites (0%) possessed an ALDH2*2 allele.  Chinese (92%) and Koreans (90%) did not differ in their possession of an ADH2*2 allele, but Whites (5%) were significantly less likely to possess an ADH2*2 allele than either Asian subgroup.  Ten percent of the sample had a history of conduct disorder. Significantly more men (17%) than women (3%) met criteria for conduct disorder,  2 (1, N = 604) = 35.94 p =.000.  Korean Americans had the highest rate of conduct disorder at 15%, followed by White Americans at 9%, and Chinese Americans at 6%,  2 (2, N = 604) = 11.12, p =.004.  12% of the sample met criteria for a lifetime diagnosis of alcohol dependence. More men (16%) than women (7%) were alcohol dependent,  2 (1, N = 604) = 12.05 p =.001.  Chinese (5%) were less likely to be diagnosed with alcohol dependence than Koreans (13%) and Whites (17%), but the rate did not significantly differ between Koreans and Whites,  2 (2, N = 604) = 14.64, p =.001.  Univariate logistic regressions (shown above) found ALDH2 status, ADH2 status, conduct disorder, being male, and ethnicity all significantly related to lifetime alcohol dependence.  Conduct disorder predated alcohol dependence in all cases but two, where the onset of the diagnoses occurred at the same age. The three steps of mediation were tested: 1. Ethnicity significantly related to alcohol dependence (step   = 16.2, p =.000). 2. In three logistic regressions, ethnicity related to ALDH2 status (   = 183.9, p =.000), to ADH2 status (   = 476.7, p =.000), and to conduct disorder (   = 11.0, p =.004) 3. ADH2 status was not significantly related to alcohol dependence with ALDH2 status entered first. Gender no longer significantly related to alcohol dependence with ALDH2 and conduct entered first. No interactions were significant. Thus, ADH2 status and gender were removed from further analyses. Next, ethnicity was not significantly related to alcohol dependence after ALDH2 status and conduct disorder were entered (step   = 5.80, p =.055; see Step 3 Table). Additional logistic regressions were conducted examining the effect of each ethnic group compared to the other two groups combined (3a, 3b, 3c). White and Korean ethnicity were not related to alcohol dependence, but Chinese ethnicity was (step   = 4.79, p =.029). No interactions were significant. Summary of Findings Univariate Multivariate