Evaluation of aldehyde dehydrogenase 1 promoter polymorphisms identified in human populations

Human aldehyde dehydrogenase 1 (ALDH1A1) functions as an important enzyme in both the metabolism of acetaldehyde and the synthesis of retinoic acid (Elizondo et al., 2000; Ueshima et al., 1993). ALDH1A1 also has been implicated in several alcohol-related phenotypes, including alcoholism, alcohol-induced flushing, and alcohol sensitivity (Chan, 1986; Yoshida, 1992). Studies suggest that low ALDH1A1 activity may contribute to alcohol sensitivity and alcohol-induced flushing in Caucasians and some Asians (Ward et al., 1994; Yoshida et al., 1989). Adverse reactions resulting from reduced ALDH1A1 function may be influencing the predisposition for alcoholism in non-Asian populations (Eriksson, 2001). In fact, a study has identified a polymorphism in the coding region of ALDH1A1 that contributes to ethanol preference in high alcohol-preferring (HAP)/low alcohol-preferring (LAP) rats, suggesting that a functionally altered ALDH1A1 influences alcohol consumption in an animal model (Negoro et al., 1997; Nishiguchi et al., 2002). Due to its involvement in ethanol metabolism, ALDH1A1 is an interesting candidate for alcohol research. Multiple aldehyde dehydrogenase isozymes have been characterized that exhibit similar functional properties implicated in ethanol detoxification, including ALDH1A1, ALDH1B1, ALDH2, and ALDH3A1 (Vasiliou and Pappa, 2000; Yoshida, 1992). The mitochondrial form of aldehyde dehydrogenase, or ALDH2, has been associated with a reduced incidence of alcoholism in certain Asian populations (Higuchi et al., 1995). In these populations, a functional polymorphism in ALDH2 leads to acetaldehyde accumulation, resulting in alcohol-induced flushing (Takeshita et al., 1994), but the underlying mechanism influencing alcoholic predisposition is still unknown (Li, 1997). The ALDH2 enzyme exhibits a higher affinity for acetaldehyde and primarily oxidizes acetaldehyde in humans (Klyosov et al., 1996); however, the functions of the ALDH isozymes in the central nervous system remain unclear (Stewart et al., 1996; Tank et al., 1986). The promoter region contains regulatory binding sites that are involved in gene expression and tissue specificity (Mitchell and Tjian, 1989). Mutations in regulatory binding sites can substantially affect gene regulation, altering enzyme levels that can ultimately contribute to phenotypic variability throughout a population. Polymorphism in the ALDH1A1 promoter region could affect the steady-state levels of ALDH1A1 and alter acetaldehyde and retinoid metabolism. Thus far, variants of the regulatory region in the promoter of the ALDH1A1 gene have not yet been studied. Although previous studies indicate that ALDH1A1 may contribute to alcoholism, alcohol sensitivity, and alcohol-induced flushing, no definitive evidence has been provided to adequately link ALDH1A1 to these phenotypes. The purpose of this study was to identify human ALDH1A1 promoter polymorphisms, to determine their functional significance, and to screen for associations between these polymorphisms and alcoholism.