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BackgroundEpidemiological research on dementia is hampered by differences across studies in how dementia is classified, especially where clinical diagnoses of dementia may not be available.ObjectiveWe apply structural equation modeling to estimate dementia likelihood across heterogeneous samples within a multi-study consortium and use the twin design of the sample to validate the results.MethodsUsing 10 twin studies, we implement a latent variable approach that aligns different tests available in each study to assess cognitive, memory, and functional ability. The model separates general cognitive ability from components indicative of dementia. We examine the validity of this continuous latent dementia index (LDI). We then identify cut-off points along the LDI distributions in each study and align them across studies to distinguish individuals with and without probable dementia. Finally, we validate the LDI by determining its heritability and estimating genetic and environmental correlations between the LDI and clinically diagnosed dementia where available.ResultsResults indicate that coordinated estimation of LDI across 10 studies has validity against clinically diagnosed dementia. The LDI can be fit to heterogeneous sets of memory, other cognitive, and functional ability variables to extract a score reflective of likelihood of dementia that can be interpreted similarly across studies despite diverse study designs and sampling characteristics. Finally, the same genetic sources of variance strongly contribute to both the LDI and clinical diagnosis.ConclusionThis latent dementia indicator approach may serve as a model for other research consortia confronted with similar data integration challenges.

BackgroundAn early age of drinking initiation (ADI) has been associated with increased risk for alcohol use disorders (AUDs), but the consistency of this risk across diverse samples has not been well studied. The purpose of this study was to examine whether the pathway from ADI to AUD symptoms by early adulthood is moderated by ethnicity and possessing an alcohol-metabolizing gene ALDH2*2 variant allele.MethodsWe used multigroup structural equation modeling, including 5 groups split by ethnicity and ALDH2*2, to examine the consistency of the path from ADI to AUD symptoms in 604 Chinese-, Korean-, and White-American college students. We further examined the effects of ALDH2*2, ethnicity, and their interaction in Asians to better understand their unique contributions to the moderation.ResultsThe association between ADI and AUD symptoms was moderated, with ADI negatively associated with AUD symptoms among Koreans without ALDH2*2 and Whites, but not among Koreans with ALDH2*2 or Chinese regardless of ALDH2*2. Both ALDH2*2 and ethnicity within Asians contributed unique variability in the effect.ConclusionsEthnicity and ALDH2*2 altered the relationship of ADI as a risk factor for AUD symptoms. Being Chinese and possessing an ALDH2*2 allele within Koreans both buffered against the risk for AUD symptoms associated with earlier ADI, indicating that this relationship can be attenuated by protective factors.

FKBP5 encodes FK506-binding protein 5, a glucocorticoid receptor (GR)-binding protein implicated in various psychiatric disorders and alcohol withdrawal severity. The purpose of this study is to characterize alcohol preference and related phenotypes in Fkbp5 knockout (KO) mice and to examine the role of FKBP5 in human alcohol consumption. The following experiments were performed to characterize Fkpb5 KO mice. (1) Fkbp5 KO and wild-type (WT) EtOH consumption was tested using a two-bottle choice paradigm; (2) The EtOH elimination rate was measured after intraperitoneal (IP) injection of 2.0 g/kg EtOH; (3) Blood alcohol concentration (BAC) was measured after 3 h limited access of alcohol; (4) Brain region expression of Fkbp5 was identified using LacZ staining; (5) Baseline corticosterone (CORT) was assessed. Additionally, two SNPs, rs1360780 (C/T) and rs3800373 (T/G), were selected to study the association of FKBP5 with alcohol consumption in humans. Participants were college students (n = 1162) from 21-26 years of age with Chinese, Korean or Caucasian ethnicity. The results, compared to WT mice, for KO mice exhibited an increase in alcohol consumption that was not due to differences in taste sensitivity or alcohol metabolism. Higher BAC was found in KO mice after 3 h of EtOH access. Fkbp5 was highly expressed in brain regions involved in the regulation of the stress response, such as the hippocampus, amygdala, dorsal raphe and locus coeruleus. Both genotypes exhibited similar basal levels of plasma corticosterone (CORT). Finally, single nucleotide polymorphisms (SNPs) in FKBP5 were found to be associated with alcohol drinking in humans. These results suggest that the association between FKBP5 and alcohol consumption is conserved in both mice and humans.

Background and objectivesThis study examined gambling behaviors and the relationship between gambling problems and alcohol use disorders (AUDs) among Chinese-, Korean-, and White-American college students.MethodsParticipants were 678 (179 Chinese, 194 Korean, and 305 White; 50% female) 21-26 year-old (M = 22.0 ± 1.36) students attending one university in California. The South Oaks Gambling Screen was administered to assess gambling behavior and the Semi-Structured Assessment for the Genetics of Alcoholism was administered to diagnose lifetime AUDs. Chi-squares and multinomial logistic regressions were conducted to test our hypotheses.ResultsRates of lifetime ever gambling and weekly gambling were similar across the three ethnic groups, but participation in five types of gambling behavior differed. Chinese had the highest rates of gambling problems followed by Koreans and then Whites. Univariate odds ratios determined being Chinese or Korean, being male, and having an AUD were risk factors for gambling problems. When stratified by gender and ethnicity, having an AUD was not related to gambling problems in women, but was strongly associated with gambling problems in Chinese and White men and modestly associated in Korean men. This was true despite low rates of AUDs in Chinese men.Discussion and conclusionsGambling problems were strongly comorbid with AUDs in Chinese- and White-American men, and moderately comorbid in Korean-American men. No relationship of AUD with gambling problems was found in women.Scientific significanceThe results highlight the importance of assessing disaggregated Asian-American subgroups with respect to addictive behaviors and their comorbidity.

Gene variants encoding several of the alcohol-metabolizing enzymes, alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH), are among the largest genetic associations with risk for alcohol dependence. Certain genetic variants (i.e., alleles)--particularly the ADH1B*2, ADH1B*3, ADH1C*1, and ALDH2*2 alleles--have been associated with lower rates of alcohol dependence. These alleles may lead to an accumulation of acetaldehyde during alcohol metabolism, which can result in heightened subjective and objective effects. The prevalence of these alleles differs among ethnic groups; ADH1B*2 is found frequently in northeast Asians and occasionally Caucasians, ADH1B*3 is found predominantly in people of African ancestry, ADH1C*1 varies substantially across populations, and ALDH2*2 is found almost exclusively in northeast Asians. Differences in the prevalence of these alleles may account at least in part for ethnic differences in alcohol consumption and alcohol use disorder (AUD). However, these alleles do not act in isolation to influence the risk of AUD. For example, the gene effects of ALDH2*2 and ADH1B*2 seem to interact. Moreover, other factors have been found to influence the extent to which these alleles affect a person's alcohol involvement, including developmental stage, individual characteristics (e.g., ethnicity, antisocial behavior, and behavioral undercontrol), and environmental factors (e.g., culture, religion, family environment, and childhood adversity).

BackgroundHealth disparities research seeks to eliminate disproportionate negative health outcomes experienced in some racial/ethnic minority groups. This brief review presents findings on factors associated with drinking and alcohol-related problems in racial/ethnic groups.MethodsThose discussed are as follows: (i) biological pathways to alcohol problems, (ii) gene × stress interactions, (iii) neighborhood disadvantage, stress, and access to alcohol, and (iv) drinking cultures and contexts.ResultsThese factors and their interrelationships are complex, requiring a multilevel perspective.ConclusionsThe use of interdisciplinary teams and an epigenetic focus are suggested to move the research forward. The application of multilevel research to policy, prevention, and intervention programs may help prioritize combinations of the most promising intervention targets.

The variant aldehyde dehydrogenase allele, ALDH2∗2, consistently has been associated with protection against alcohol dependence, but the mechanism underlying this process is not known. This study examined growth trajectories of alcohol consumption (frequency, average quantity, binge drinking, maximum drinks) and problems over the college years and then tested whether the ALDH2 genotype mediated or moderated the relationship between alcohol consumption and problems. Asian American college students (N = 433) reported on their drinking behavior in their first year of college and then annually for 3 consecutive years. Alcohol consumption and problems increased over the college years for both those with and without ALDH2∗2, but having an ALDH2∗2 allele was associated with less of an increase in problems over time. A mediation model was supported, with ALDH2∗2 group differences in problems fully accounted for by differences in frequency of binge drinking. Findings also supported a moderation hypothesis: All four alcohol consumption variables were significant predictors of subsequent alcohol problems, but these relationships were not as strong in those with ALDH2∗2 as in those without ALDH2∗2. Our findings suggest that the interplay between ALDH2∗2 and drinking-related problems is complex, involving both mediation and moderation processes that reduce the likelihood of developing problems via reduction of heavy drinking as well as by altering the relationship between alcohol consumption and problems. Results of this longitudinal study provide evidence that what seems like a relatively straightforward effect of a diminished ability to metabolize alcohol on drinking behavior is actually dependent on behavior and developmental stage.

Variants of three genes encoding alcohol-metabolizing enzymes, the aldehyde dehydrogenase gene ALDH2 and the alcohol dehydrogenase genes ADH1B and ADH1C, have been associated with reduced rates of alcohol dependence. The genotype prevalence of these genes varies in general samples of different Asian ethnic groups. The ALDH2*2 allele appears to be most prevalent in Chinese-American, Han Chinese and Taiwanese, Japanese, and Korean samples. Much lower rates have been reported in Thais, Filipinos, Indians, and Chinese and Taiwanese aborigines. ADH1B*2 is highly prevalent among Asians, with the exception of Indians. ADH1C*1 also is highly prevalent in Asians, but has only been examined in a few studies of Chinese and Korean samples.

An output feedback linear‐quadratic Gaussian compensator (combined controller and state estimator) for the regulation of intravenous‐infused alcohol studies and treatment using a noninvasive transdermal alcohol biosensor is developed. The design is based on a population model involving an abstract semilinear parabolic hybrid reaction‐diffusion system involving coupled partial and ordinary differential equations with random parameters known only up to their distributions. The scheme developed is based on a weak formulation of the model equations in an appropriately constructed Gelfand triple of Bochner spaces wherein the unknown random parameters are treated as additional spatial variables. Implementation relies on a Galerkin‐based approximation and convergence theory and an abstract formulation involving linear semigroups of operators. The model is fit and validated using laboratory collected human subject data and the method of moments. The results of numerical simulations of controlled intravenous alcohol infusion are presented and discussed. [ABSTRACT FROM AUTHOR]

Meta-analyses were conducted to determine the magnitude of relationships between polymorphisms in 2 genes, ALDH2 and ADH1B, with alcohol dependence in Asians. For each gene, possession of 1 variant [asterisk]2 allele was protective against alcohol dependence, and possession of a 2nd [asterisk]2 allele did not offer significant additional protection. The protective effects of these 2 gene polymorphisms were independent. Diagnostic criteria, recruitment strategy, and Japanese ethnicity moderated the effect of ALDH2[asterisk]2. Recruitment strategy and gender moderated the effect of ADH1B[asterisk]2. These findings highlight the importance of methodological issues and potential gene-gene and gene-environment interactions that must be considered when examining relationships between genetic polymorphisms and phenotypes.

INDIVIDUALS OF ASIAN DESCENT comprise more than 50% of the total world population and approximately 4.4% of the population of the United States (Reeves and Bennett, 2003; World Gazetteer, 2006). [...], Objective: Koreans have higher rates of alcohol-use disorders and family history of alcoholism, compared with Chinese. These differences likely reflect both environmental and genetic influences. One genetically influenced characteristic that may contribute to these ethnic differences is level of response to alcohol. Variant alleles of aldehyde dehydrogenase (ALDH2) and alcohol dehydrogenase (ADH1B) genes are prevalent in individuals of Asian heritage and have been associated with an increased level of response to alcohol and a decreased risk for alcohol dependence. Additionally, a low level of response to alcohol is more common in individuals with a first-degree family history of alcoholism and is predictive of increased risk for this disorder. It also is possible that sociocultural factors have an impact on an individual's response to alcohol. The current study examined self-report level of response to alcohol, ALDH2 and ADH1B, country of origin, and family history of alcoholism in 154 Chinese--and 181 Korean-American college students. Method: Participants were evaluated via in-person interviews and genotyped at the ALDH2 and ADH1B loci. Results: Ethnicity was significantly related to level of response to alcohol, with Koreans having a lower self-reported level of response than Chinese. This relationship remained significant after considering the effects of gender, height, weight, quantity and frequency of alcohol consumption (over the previous 90 days), ALDH2 genotype, ADH1B genotype, country of origin, and first-degree family history of alcohol dependence. Conclusions: The results suggest that a low level of response to alcohol may contribute to the increased risk for alcohol abuse and dependence found in Koreans, relative to Chinese. More research is needed to determine additional factors that may be contributing to the low alcohol response and high rates of alcoholism in Koreans.

THE PREVALENCE OF ALCOHOL-USE DISORDERS (AUDs; i.e., alcohol abuse and dependence) and heavy episodic alcohol use vary by ethnicity. Individuals of Asian ethnicity, for example, drink less and are at [...], Objective: A previous cross-sectional study showed that, among individuals of Chinese and Korean descent, possession of ALDH2*2 alleles was associated with protection against alcohol dependence, whereas conduct disorder was associated with increased vulnerability to dependence. The purpose of this longitudinal study was to examine the roles of ALDH2 and behavioral undercontrol (a temperamental trait that is associated with conduct disorder) in stability of heavy episodic drinking. Method: Chinese- and Korean-American college students (N = 336; 51% female), who had initiated alcohol use before study enrollment, provided information on drinking habits during their freshman and sophomore years. Participants were classified as (1) stable nonheavy drinkers, (2) regressors, (3) progressors, or (4) stable heavy drinkers. Results: Participants with ALDH2*2 alleles were more likely to be classified as stable nonheavy drinkers than as progressors (z = -2.49, p = .013). Higher levels of behavioral undercontrol were associated with a greater probability of being classified as a stable heavy drinker relative to a stable nonheavy drinker (z = 2.26, p = .024). Stable heavy drinkers reported the most alcohol-related problems, whereas progressors reported more problems than either regressors or stable nonheavy drinkers, particularly at Year 2. Conclusions: Elevated behavioral undercontrol appears to predispose Asian-American college students to increased frequency of heavy drinking, whereas ALDH2*2 may act as a protective factor. The degree of alcohol consumption observed among participants with ALDH2*2 alleles is consistent with previous findings showing that, although their presence may be protective, it does not preclude heavy drinking episodes. (J. Stud. Alcohol Drugs 68: 789-797, 2007)

ALCOHOL-INDUCED BLACKOUTS (periods of anterograde amnesia without loss of consciousness) are commonly reported in both problem and nonproblem drinkers. Studies in the United States, Australia, and Scandinavia indicate approximately one [...], Objective: A recent report found the heritability estimate for alcohol-induced blackouts was 53%. The present study was designed to determine whether possession of two specific genetic variations, an aldehyde dehydrogenase ALDH2*2 allele and an alcohol dehydrogenase ADH1B*2 allele, were associated with lower rates of lifetime blackouts. Method: Asian American college students (N = 403) of Chinese and Korean descent were genotyped at the ALDH2 and ADH1B loci and assessed for lifetime alcohol-induced blackouts and the maximum number of drinks ever consumed in a 24-hour period. Results: Participants who had an ALDH2*2 allele had approximately one third the risk of having a lifetime blackout of participants without this allele. Rates of experiencing a lifetime blackout did not significantly differ by ADH1B*2 status. Possessing an ALDH2*2 allele was associated with decreased risk of lifetime blackouts even after controlling for maximum number of drinks ever consumed in a 24-hour period and ethnicity. Conclusions: These findings suggest the protective effects of possessing an ALDH2*2 allele include a lowered risk of experiencing alcohol-induced blackouts.

Associations of alcohol dehydrogenase (ADH) gene polymorphisms (ADH1B*2 and ADHIC*1) with a lifetime alcohol use disorder (AUD) were examined in White college students. Alcohol-related endophenotypes likely to be influenced by elevations in acetaldehyde were also assessed. Individuals with an ADH1B*2 allele had lower rates of AUDs, consumed a lower maximum number of drinks in a 24-hr period, reported a greater level of response to alcohol, were more likely to have experienced alcohol-induced headaches following 1 or 2 drinks, and reported more severe hangovers than those lacking this allele. These findings are consistent with the hypothesis that enhanced sensitivity to alcohol and lower levels of alcohol use reflect the mechanism by which ADH1B*2 protects against developing an AUD. Keywords: ADH, alcohol abuse, alcohol dependence, phenotype

IT IS ESTIMATED THAT genetic factors account for approximately 50 to 60% of the variability in risk for developing alcohol dependence (Heath et al., 1997; Prescott et al., 1999). One [...], Objective: Individuals with alcohol dependence are less likely to possess variant alleles of the alcohol-metabolizing genes, aldehyde dehydrogenase (ALDH2*2) and alcohol dehydrogenase (ADH1B*2), than non-alcohol-dependent controls. It is hypothesized that the mechanism through which these alleles protect against alcohol dependence is by causing elevations in acetaldehyde, which in turn cause an increased response to alcohol. Previous research has shown that individuals with ALDH2*2 demonstrate enhanced reactions to alcohol compared with those without this genetic variant, but evidence that ADH1B*2 is associated with a greater alcohol response is mixed. This study was designed to determine whether the ADH1B genotype is associated with more intense reactions to alcohol after controlling for the ALDH2 genotype. Method: Participants (N = 101) were Asian American college students. Each was evaluated using objective and subjective measures before and after ingestion of alcohol and placebo beverages. Results: Participants with the ALDH2*1/*2 and ALDH2*2/*2 genotypes were more likely to experience vomiting following ingestion of the alcohol beverage than those with the ALDH2*1/*1 genotype. Participants with the ALDH2*1/*2 genotype also had greater pulse-rate increases, observed flushing ratings, and subjective feelings of intoxication 30 minutes after ingestion of alcohol than participants with the ALDH2*1/*1 genotype, despite equivalent blood alcohol concentration (BAC) measurements. Among participants with the ALDH2*1/*1 genotype, there were no additional effects of the ADH1B genotype on any measures of response to alcohol. Among participants with the ALDH2*1/*2 genotype, those with the ADH1B*2/*2 genotype were more likely to experience alcohol-induced vomiting and to report feeling less 'great overall' 30 minutes after ingestion of alcohol than those with the ADH1B*1/*2 genotype. Conclusions: These findings are consistent with the hypothesis that there is an additional effect of ADH1B*2 on level of response to alcohol, hut only among individuals with the ALDH2*1/*2 genotype.

This study examined aldehyde dehydrogense (ALDH2) gene status, alcohol dehydrogense (ADH2) gene status, conduct disorder, and alcohol dependence in Chinese, Korean, and White American college students. Chinese had a lower rate of alcohol dependence (5%) than Koreans (13%) and Whites (17%). Koreans had a higher rate of conduct disorder (15%) than Whites (9%) and Chinese (6%). The relationship of ethnicity to alcohol dependence was mediated by ALDH2 status and conduct disorder, although Chinese ethnicity remained significant. ADH2 status was not related to alcohol dependence with ALDH2 included, and no interactions were significant. Results suggest that different rates of risk (e.g., conduct disorder) and protective (e.g., ALDH2 status) factors partially account for ethnic differences in rates of alcohol dependence.

HEAVY EPISODIC (binge) drinking in college students is a growing focus of attention in the alcohol research literature (Goldman et al., 2002). Heavy drinking episodes (defined as five or more [...], Objective: The purpose of the current study was to examine religious influences that relate to heavy episodic drinking in Chinese-American and Korean-American college students, after controlling for the effects of ALDH2 gene status. Method: Participants (159 Chinese-American and 188 Korean-American college students) were assessed for the presence or absence of a heavy drinking episode in the past 2 weeks, using a gender-specific measure. All participants also reported their religious affiliation and the number of religious services attended in the past year, and were genotyped at the ALDH2 locus. Results: Chinese were less likely than Koreans to be affiliated with any religion (55% vs 84%), but were more likely to be affiliated with Eastern religions (12% vs 1%). When controlling for the effects of ALDH2 status, service attendance significantly related to lower rates of heavy episodic drinking in Koreans, but did not reach significance in Chinese. The relationship was significant, however, in Chinese affiliated with Western religions. In addition, religious service attendance only related to heavy drinking in individuals with ALDH2*1/*1 genotype. Conclusions: These results suggest religious service attendance is inversely related to heavy episodic drinking in Korean Americans and in Chinese Americans with Western religious affiliation. Moreover, service attendance appears to more strongly influence heavy drinking in individuals who are not already protected by an ALDH2*2 allele.