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ALDH2 and ADH1B Interactions in Retrospective Reports of Low-Dose Reactions and Initial Sensitivity to Alcohol in Asian American College Students

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ALDH2 and ADH1B Interactions in Retrospective Reports of Low-Dose Reactions and Initial Sensitivity to Alcohol in Asian American College Students Alcoholism: Clinical and Experimental Research Vol. 35, No. 7 July 2011 ALDH2 and ADH1B Interactions in Retrospective Reports of Low-Dose Reactions and Initial Sensitivity to Alcohol in Asian American College Students Susan E. Luczak, Danielle Pandika, Shoshana H. Shea, Mimy Y. Eng, Tiebing Liang, and Tamara L. Wall Background: A mechanistic model has been proposed for how alcohol-metabolizing gene vari- ants protect individuals from the development of alcohol use disorders, with heightened sensitivity to alcohol being an early step (endophenotype) in this model. This study was designed to determine whether possession of 2 alcohol-metabolizing genes variations, the aldehyde dehy- drogenase ALDH2*2 allele and the alcohol dehydrogenase ADH1B*2 allele, was associated with self-reported sensitivity to alcohol at low doses and at initial use. Methods: Asian–American college students (N = 784) of Chinese and Korean descent were genotyped at the ALDH2 and ADH1B loci and assessed for lifetime alcohol symptoms following 1 or 2 drinks and level of response to alcohol during the first 5 lifetime drinking episodes. Results: Participants who had an ALDH2*2 allele were more likely to report experiencing all 6 low-dose symptoms and having heightened initial response to alcohol. An interaction was found between ALDH2*2 and ADH1B*2, with ADH1B*2 being associated with heightened self-reported sensitivity to alcohol only in individuals who also possessed 1 ALDH2*2 allele. Conclusions: These findings suggest the effects of ADH1B*2 may be felt more strongly in Asians who already have some heightened sensitivity to alcohol from possessing 1 ALDH2*2 allele, but who are not too sensitized to alcohol from possessing 2 ALDH2*2 alleles. These results offer additional insight into the discrepant findings that have been reported in the literature for the role of ADH1B*2 in response to alcohol and the development of alcohol-related problems. Key Words: ALDH2, ADH1B, Alcohol-Metabolizing Genes, Gene–Gene Interaction, Alcohol Sensitivity, Subjective Response to Alcohol. HE ETIOLOGY OF alcohol use disorders (AUDs; and then to acetate by aldehyde dehydrogenase. The ALDH2 T alcohol abuse and dependence) is complex, with (rs671) gene codes for the primary liver isoenzyme involved in approximately 50 to 60% of the risk being attributed to the conversion of acetaldehyde to acetate. ALDH2 has 2 alle- genetic factors (Heath et al., 1997; Prescott et al., 1999). Poly- lic forms, the wild-type ALDH2*1 (ALDH2*Glu487)andthe morphic genes, including the aldehyde dehydrogenase gene variant ALDH2*2 (ALDH2*Lys487). ALDH2*2 is extremely ALDH2 (12q24) and the alcohol dehydrogenase gene ADH1B rare in non-Asians, but present in about 30 to 50% of north- (4q22), have been proposed as particularly compelling alco- eastern Asians (Chinese, Koreans, Japanese) with a small per- hol-specific genes associated with AUDs (Li, 2000). centage (about 5%) homozygous for this allele (Goedde In the primary pathway of alcohol metabolism, alcohol is et al., 1992). ALDH2*2 has been consistently and strongly initially converted to acetaldehyde by alcohol dehydrogenase associated with decreased rates of alcohol-related problems and AUDs. In a meta-analysis, having 1 ALDH2*2 allele was From the Department of Psychology, University of Southern Cali- associated with a 4- to 5-fold reduction in alcohol dependence fornia (SEL), Los Angeles, California; Department of Psychiatry, (odds ratio, OR = 0.22) and having 2 ALDH2*2 alleles was University of California (SEL, DP, SHS, TLW), San Diego, Califor- associated with an 8- to 9-fold reduction in alcohol depen- nia; Veterans Affairs San Diego Healthcare System (SHS, TLW), dence (OR = 0.12; Luczak et al., 2006). San Diego, California; Veterans Medical Research Foundation (MYE, TLW), San Diego, California; and Departments of Medicine The alcohol dehydrogenase ADH1B (rs1229984) gene and Pharmacology, Indiana University (TL), Indianapolis, Indiana. codes for the primary isoenzyme involved in the conversion Received for publication September 5, 2010; accepted December 1, of alcohol to acetaldehyde. In Asians, ADH1B has 2 allelic 2010. forms, the wild-type ADH1B*1 (ADH1B*47Arg)andthevar- Reprint requests: Tamara L. Wall, PhD, Psychology Service iant ADH1B*2 (ADH1B*47His).ADH1B*2is found in (116B), Veterans Affairs San Diego Healthcare System, 3350 La Jolla Village Drive, San Diego, CA 92161; Tel.: 858-552-8585, ext nearly 90% of northeast Asian populations and in lower prev- 2485; Fax: 858-642-6201, E-mail: [email protected] alence in Caucasians (about 5 to 10%, although in higher Copyright Ó 2011 by the Research Society on Alcoholism. rates in Eastern European Jews and Russians; Borras et al., DOI: 10.1111/j.1530-0277.2011.01458.x 2000; Goedde et al., 1992; Ogurtsov et al., 2001). ADH1B*2 1238 Alcohol Clin Exp Res, Vol 35, No 7, 2011: pp 1238–1245 ALCOHOL-METABOLIZING GENES AND ALCOHOL SENSITIVITY 1239 also has consistently been associated with lower rates of alco- 1992, 1994). These heightened responses to alcohol are found hol dependence. This relationship is found after controlling even at low doses of alcohol, with possession of 2 ALDH2*2 for ALDH2*2 in Asian subgroups (Luczak et al., 2006) and alleles resulting in even more intense responses than posses- in European Caucasian subgroups (Borras et al., 2000; Ogurt- sion of 1 ALDH2*2 allele (Peng et al., 1999, 2002). sov et al., 2001; Wall et al., 2005; Whitfield, 2002). In a meta- Findings for the proposed relationship between ADH1B*2 analysis of the effect of ALDH2*2 and ADH1B*2 alleles in and increased sensitivity to alcohol have been less consistently combination in Asians (Luczak et al., 2006), ALDH2*1 ⁄*1 supported by data. Some studies of Asians (Chen et al., 1998; individuals with 1 ADH1B*2 allele had about one-fourth Matsuo et al., 2006), Jews (Carr et al., 2002), and non-Jewish (OR = 0.26) and those with 2 ADH1B*2 alleles had about Caucasians (Macgregor et al., 2009; Wall et al., 2005) find one-fifth (OR = 0.20) the risk of alcohol dependence individuals with ADH1B*2 alleles retrospectively self-report compared with individuals with no ADH1B*2 alleles. In more intense reactions to alcohol (e.g., flushing, headaches, ALDH2*1 ⁄*2 individuals, those with 1 ADH1B*2 allele had nausea, palpitations, and other alcohol-related symptoms) about one-sixth (OR = 0.17) and those with 2 ADH1B*2 than participants without an ADH1B*2 allele, but other stud- alleles had about one-eleventh (OR = 0.09) the risk of alco- ies do not relate ADH1B*2 to self-reports of a heightened hol dependence compared with individuals with no ADH1B*2 response to alcohol (Shea et al., 2001; Takeshita et al., 1994). alleles. In an earlier meta-analysis, Whitfield (2002) found Similarly, an alcohol challenge study of non-Asians (Cauca- similar protective effects of ADH1B*2 in Asians, but in Cau- sians and African Americans) supported ADH1B*2 leading casians the protection from possessing 1 ADH1B*2 allele was to heightened responses to alcohol (Duranceaux et al., 2006), only about half (OR = 0.47). These results suggest ALDH2 but other alcohol challenge studies of Asians (Peng et al., and ADH1B each contribute unique protective effects on 2002) and Caucasians (Heath et al., 1999) have not found sig- alcohol dependence, and the level of protection may be even nificant effects of ADH1B*2 on measures of intoxication and stronger in conjunction than alone. flushing. Several studies of Asians using alcohol challenge, A mechanistic pathway has been proposed for how possess- retrospective self-report, and skin patch tests have reported ing ALDH2*2 and ADH1B*2 alleles may reduce an individ- ADH1B*2 is associated with increased alcohol-related symp- ual’s risk for alcohol dependence (Eriksson, 2001; Li, 2000; toms (e.g., facial flushing, vomiting), but that this relationship Thomasson et al., 1991; see Wall, 2005). Based on their is only significant in individuals who also possess an kinetic properties, ADH1B*2 should lead to faster production ALDH2*2 allele (Cook et al., 2005; Takeshita et al., 1996, of acetaldehyde than ADH1B*1 (Bosron and Li, 1986) and 2001; Yokoyama et al., 1999, 2003; although see Chen et al., ALDH2*2 should lead to slower elimination of acetaldehyde 1998), suggesting it may be the combined effects of ALDH2*2 than ALDH2*1 (Wilkin, 1981). These increased acetaldehyde and ADH1B*2 that lead to more apparent associations of levels are hypothesized to lead to heightened responses to these alleles with response to alcohol. alcohol, which in turn are predicted to discourage heavy alco- In this study, we used retrospective self-report measures to hol consumption. Lower alcohol consumption is then pro- assess low-dose and initial sensitivity to alcohol in Asian par- posed to reduce the likelihood of an individual developing an ticipants with varying ALDH2 and ADH1B genotypes. We AUD. Although there is much evidence to support this mech- first examined the effects of ALDH2*2 alone, then after test- anism for ALDH2*2, the data supporting this mechanism for ing ALDH2-ADH1B interactions we controlled for ALDH2 ADH1B*2 has been less consistent (Eriksson, 2001; see Wall, to determine whether the intensity of response to alcohol also 2005). This study was undertaken to better understand early differed across ADH1B genotypes. It was predicted that steps of the mechanistic pathway relating ALDH2 and ALDH2*2 would be associated with higher rates of alcohol- ADH1B polymorphisms to lower rates of AUDs. The pri- related symptoms. In addition, it was predicted that if mary objective was to clarify associations of ALDH2 and ADH1B polymorphisms were related to a more intense ADH1B variations with low-dose reactions and initial sensi- response to alcohol (i.e., alcohol sensitivity), then participants tivity to alcohol. homozygous for ADH1B*2 would report the most alcohol- ALDH2*2 has been related to alcohol sensitivity as mea- related symptoms while participants heterozygous for sured by retrospective self-reports of flushing and other symp- ADH1B*2 would report more alcohol-related symptoms than toms (e.g., headaches, heart palpitations, drowsiness) those without the variant allele.
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