Alcoholism is a complex, multi-factoral disorder with likely underlying genetic and environmental factors (Enoch et al., 2003; Kimura et al., 2009; Shin et al., 2009). Alcohol use is very common in our society. According to the Centers for Disease Control and Prevention (CDC), drinking alcohol can impair judgment, which increases the risk for drunken driving accidents and other harmful decisions. Alcohol consumption can also contribute to other conditions such as "liver disease, heart disease, high blood pressure, lowered immune system and malnutrition" (CDC, 2010). Besides an increased risk for certain medical conditions, alcohol consumption can also cause immediate harmful effects. Between the years of 2001 and 2005, there were approximately 79,000 deaths annually attributed to excessive alcohol use (CDC, 2010). In fact, alcohol use is the third leading lifestyle related case of death in the United States each year (CDC, 2010).
It is through the use of globally accepted definitions and diagnostic criteria of alcohol disorders that we can examine the degree to which alcohol misuse becomes a problem in an individual's life. According to the DSM-IV, the criteria for alcohol dependence includes a "maladaptive pattern of alcohol use, leading to clinically significant impairment or distress," and the continued use of alcohol "despite knowledge of having a persistent or recurrent physical or psychological problem that is likely to have been caused or exacerbated by the alcohol" (DSM-IV; American Psychiatric Association, 1994).
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One pertinent example of continued alcohol consumption despite recurrently physical problems cause of exacerbated by alcohol are the alcoholics who have developed alcoholism despite one particular strong negative risk factor. That is, the inactive form of aldehyde dehydrogenase-2 (ALDH2). The polymorphism of ALDH2 is a well-known genetic determinant of alcoholism. Inactive ALDH2 causes a high acetaldehyde level after drinking. This physical reaction will be later explained in further detail. The main point, however, is individuals with the inactive ALDH2 experience, when drinking, unpleasant symptoms such as flushing, nausea, and headache, which function to suppress drinking behavior (Higuchi et al., 1996; Muramatsu et al., 1995) and the occurrence of alcoholism (Harada et al., 1982; Higuchi et al., 1994). The homozygotes of the inactive type of ALDH2 allele (ALDH2*2) prevent individuals from becoming. Furthermore, research supports the idea that the incidence of alcoholism among heterozygotes of the ALDH2 allele is much lower than among homozygotes of the active ALDH2 allele (ALDH2*1). It would be advantageous to learn more about subjects that show reduced heterogeneity and yet still possess factors that confer susceptibility to alcoholism. In other words, we could benefit from studying these individuals in order to study predisposing factors for alcoholism because people who develop alcoholism despite having the inactive ALDH2 must have some other factors that drive them to drink.
Identifying the factors that lead to alcoholism may help to prevent alcohol-related problems and lead to treatments for the disease. The presence of functional polymorphisms in genes encoding the enzymes involved in ethanol metabolism has been demonstrated in recent research (Kang et al., 2008). The metabolism of ethanol mostly occurs in the liver (Kang et al., 2008). In the liver, ethanol is mainly oxidized by alcohol dehydrogenase (ADH) and cytochrome P450 2E1 (CYP2E1) to acetaldehyde, which is then oxidized by aldehyde dehdrogenase (ALDH) to acetic acid (Kang et al., 2008). In other words, ALDH converts aldehyde to acetate in alcohol metabolism. The gene that encodes ALDH2 in humans is polymorphic (ALDH2*1 and ALDH2*2), with ALDH*2 being particularly common among east Asian peoples (Shin et al., 2009). In most previous research, it was found that ALDH*2 allele frequency is significantly lower east Asian people with AUD because, as the inactive form, presence of the ALDH*2 allele delays the elimination of acetaldehyde resulting in facial flushing and other unpleasant symptoms after drinking (Crabb et al., 1989; Thomasson et al., 1991; Chai et al., 2005; Choi et al., 2006; Shin et al., 2009). As previously stated, alcoholics who have developed alcoholism despite this strong negative risk factor (the inactive form of aldehyde dehydrogenase-2, or ALDH2) would be particularly advantageous for studying predisposing factors for alcoholism, and alcohol use disorders (AUD). There must be other underlying factors that motivate drinking behavior in these individuals. Additionally, from presence of recurring negative physical consequences, it can also be assumed that this underlying motivators and risk-facts must also be strong and, most likely, were present early on in life when problematic drinking-behavior typically emerges.
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Despite alcoholism being quite common, the disorder has both complex origins and outcomes. The factors that influence the development of alcoholism and other diseases related to alcohol, such as Alcohol Use Disorder (AUD), include many factors such as physiological factors (for example, age and biological sex), social factors, individual preferences for alcohol use as well as other factors that may also be involved. One thing that is known for certain, though, is that family and twin studies have shown that an individual's risk of alcoholism is influenced by both genetic and environmental factors (Gemma, Vichi & Testai, 2006; Kang et al., 2008). Furthermore, ethnic differences in metabolizing, or elimination, of ethanol allow us to estimate the importance of genetic factors in alcohol metabolism as well. As discussed earlier, recent pharmacogenetic research has provided valuable scientific insight. It has been demonstrated that the presence of functional polymorphisms in genes encoding the enzymes that are involved in the metabolism of ethanol. As found in Shin et al. (2009), the gene that encodes ALDH2 in humans is polymorphic: ALDH2*1 and ALDH2*2. Current and up-to-date research provides consistent results that associate allele frequencies of the polymorphisms that affect alcohol metabolism to alcoholism and other alcohol use disorders.
Alcohol use disorders (AUD) are probably one of the most common mental disorders in the United States, and are classified by the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV; American Psychiatric Association, 1994), according to a "bi-axial" approach. One axis is represented by alcohol abuse and the alcohol dependence represents the other. According to research, the heritability of AUD is approximately between 50 and 60% (Pickens et al., 1991). Despite heritability estimates, however, efforts to identify specific genes that may contribute to risk for AUD have had a limited amount of success (Kranzler et al., 2002). More recent research, however, continues to provide up-to-date information on the specific contributing genes.
Despite previously limited success, current research is working to identify specific genes that contribute to risk for alcoholism and AUD. For example, one recent study investigated the associations between alcohol use disorder and polymorphisms on ALDH2 and other alleles such as BDNF, 5-HTTLPR, and MTHFR (Shin et al., 2009). Also, another recent pharmacogenetics study compared genetic polymorphisms of CYP2E1, ADH2 and ALDH2 genes involved in alcohol metabolism in Koreans and four other ethnic groups (Kang et al., 2008).
Taking advantage of well-characterized community population with clinical assessments of AUD, a study by Shin et al. (2009) aimed to investigate the association between four candidate genes in older Korean men and AUD. The genes investigated in this study were the previously discussed ALDH2 (1 and 2), brain-derived neurotrophic factor (BDNF, val66met), serotonin transporter gene linked polymorphic region (5-HTTLPR) and methylenetetrahydrofolate reductase (MTHFR). DSM-IV criteria and clinical examinations were used to categorize a community sample of 300 men over the age of 65 into 68 subjects with AUD and 232 controls. Although no significant differences in genotype or allele frequencies were found for 5-HTTPLR or MTHFR (p>0.3), men with AUD were found to have significantly higher ALDH2*1 and BDNF met allele frequencies compared to controls (p<0.05). In other words, results suggest that AUD is associated with ALDH2*1 and BDNF met alleles in older Korean men. The first of these findings is likely to be attributed to the protective effect of the unpleasant symptoms that result from the consumption of alcohol associated with ALDH2*2, and is consistent with previous research. The second of these findings is novel, and might be explained by BDNF-mediated serotonin or dopamine pathways. It should be noted, however, that given the small sample size, the results of this study should be regarded as merely preliminary, and may benefit from replication.
Genetic factors in alcohol metabolism have been considered in the genetics of alcoholism. Recent studies are identifying functional polymorphisms in genes encoding enzymes involved in the metabolism of ethanol. Again, recent developments in pharmacogenomics have suggested that genetic polymorphisms are one of the most important factors responsible for the variation in drug metabolism between individuals. Taking these developments into consideration, Kang et al. (2008) investigated the genotype and allele frequencies of ADH2, ALDH2 and CYP2E1. These three are polymorphisms in enzymes that are likely to influence alcohol metabolism. According to various studies, it has been shown that polymorphisms in these three alcohol-metabolizing enzymes can cause individual or ethnic difference in ethanol toxicity (Crabb et al., 2004; Gemma, Vichi & Testai, 2006; Matsuo et al., 2006; Yamada et al., 2002). In Kang et al., (2008) the genotype of 342 healthy Korean volunteers was determined by extracting genomic DNA from peripheral leucocytes. Allele frequencies were compared with those of other ethnic groups registered on the International HapMap database (http://www.hapmap.org). Results show that all the combined genotype frequencies in the Korean group when compared to those of other Asian groups were similar. The combined genotype frequency for ADH2 and ALDH2, however, was higher in the Japanese population (18.2%) compared to those in the Korean and Chinese population (6.7% and 2.2% respectively). For all three alleles (AHD2, ALDH2 and CYP2E1) the combined genotype frequency tended to increase in order from the Korean (2.9%) to the Japanese (4.5%) and the Chinese (6.7%) populations. Finally, it was found that in the African and European populations, the combined genotype frequencies were 0% for all the alleles. Thus, these frequencies are very different compared to those of the Asian groups. These observations provide useful data regarding the occurrence of polymorphisms of ethanol-metabolizing enzymes. This data should be useful in assessing the comparative susceptibility of different populations to diseases related to drinking alcohol.
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As discussed earlier, patients with the inactive ALDH2 who develop alcoholism would be advantageous to study. It might be particularly beneficial to study personality factors among these subjects because of their susceptibility to alcoholism. Studies have shown an association between personality and alcohol use disorders (Mulder, 2002). A study by Kimura et al. (2009), sponsored by the Research Society on Alcoholism, hypothesized that personality traits associated with alcoholism could be explained by finding characteristics of alcoholics with inactive ALDH2. As stated, the aim of this study is to identify the clinical and personality profile of alcoholics with inactive ALDH2 compared to those with active ALDH2. ALDH2 genotypes were determined in 460 male Japanese alcoholics by polymerase chain-reaction-restriction fragment length polymorphism method. While 394 patients had the active form, 66 patients had the inactive form on ALDH2. It should be noted that all patients underwent interviews to obtain data on personalities and clinical characteristics. Results shows that alcoholics with inactive ALDH2 had significantly higher novelty-seeking and lower harm-avoidance scores compared with active ALDH2 patients. These results suggests that high novelty-seeking and low harm-avoidance scores in alcoholics with inactive ALDH2 could result in a higher risk of developing alcoholism, despite the body's low ability to reduce levels of acetaldehyde. In order to detect environmental and personality factors related to alcoholism, it may be beneficial to study alcoholics with the inactive ALDH2.
Discussion of Research
In the study conducted by Shin et al. (2009), it is interesting that out of the 68 cases with AUD, two were found with homozygotic ALDH2*2 genotypes. A previous study conducted by Chen et al., (1999) found only one homozygote out of 420 cases of AUD. Higuchi et al. (1994) states that it may be the case that the protection against AUD associated with homozygous ALDH2*2 allele is powerful, but may not be as complete as it was previously thought to be in East Asians (Higuchi et al., 1994). Besides the Shin et al. study, two other studies have investigated the association between this gene and AUD. These previous studies, however, found much smaller effect sizes and non-significant findings (Matsushita et al., 2004; Tsai et al., 2005). Matsushita et al., (2004), a Japanese case-control study, did not report an association with AUD, but did find, however, that the met allele was associated with an earlier age of onset of AUD, along with an increase in violent behavior (Matsushita et al., 2004). Additionally, it may be beneficial to replicate these results from other world regions for generalization purposes.
The results from Kang et al. (2008) show that the polymorphisms of ALDH2 are important factors associated with alcoholism and alcoholic liver disease. Individuals with the ALDH2*2 allele have levels of acetaldehyde in the blood compared to individuals with the ALDH2*1 allele (Thomasson et al., 1994) because ALDH2*2 encodes an inactive enzyme. Furthermore, a case-controlled subject conducted by Lee et al., (2001) showed that ALDH2*2 protected individuals against the development of alcoholism, but was not associated with alcoholic cirrhosis (Lee et. al., 2001).
The combined data for the genes that encode enzymes that influence the metabolism of alcohol in Kang et al. (2008) show that the genotype frequencies in Asian people are significantly different from those in Europeans and Africans but are similar among Asian populations. The results from this study could be used to assess different populations' susceptibility to diseases related to drinking. They could be helpful in the forming of strategies to reduce the risks posed by alcohol consumption.
In Kimura et al. (2009), high novelty-seeking (NS) and low harm-avoidance (HA) scores were associated with an increased risk for alcoholism in alcoholics with inactive ALDH2. This suggests that high NS and low HA might be predisposing factors for alcoholism. It was also noted in this study that those with the inactive ALDH2 revealed a low familial-history of alcoholism. Perhaps a model of alcoholics with inactive ALDH2 versus active ALDH2 may helpful when looking for possible environmental or personality factors related to alcoholism. But in spite of available research, a personality profile associated with AUD is not well-established. One challenge to identifying such a personality profile is that alcoholism is a heterogenic disease. It may be difficult to identify a particular factor related to alcoholism because of the variety of subtypes that are associated with different personality characteristics.
Fortunately, recent reports show an association between gene variation and the results of treatment of psychosocial therapies and medications (Anton et al., 2008; Bauer et al., 2007). Unfortunately, however, little is currently known about the treatment outcome for patients with inactive ALDH2 (Kimura et al., 2009). Further research is needed is needed to select the best treatment for each patient type.