Alternative titles; symbols
Other entities represented in this entry:
HGNC Approved Gene Symbol: ALDH2
Cytogenetic location: 12q24.12 Genomic coordinates (GRCh38): 12:111,766,933-111,817,532 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 12q24.12 | {Esophageal cancer, alcohol-related, susceptibility to} | 3 | ||
| {Hangover, susceptibility to} | 610251 | Autosomal dominant | 3 | |
| {Sublingual nitroglycerin, susceptibility to poor response to} | 3 | |||
| Alcohol sensitivity, acute | 610251 | Autosomal dominant | 3 |
Acetaldehyde dehydrogenase (EC 1.2.1.3) is the next enzyme after alcohol dehydrogenase (see 103700) in the major pathway of alcohol metabolism. There are 2 major ALDH isozymes in the liver: cytosolic ALDH1 (ALDH1A1; 100640) and mitochondrial ALDH2.
Hsu et al. (1985) isolated partial cDNA clones of ALDH1 and ALDH2 from a human liver cDNA library. Hsu et al. (1988) isolated and characterized ALDH2 genomic clones. The deduced ALDH2 protein contains 517 amino acids, including a 17-amino acid signal peptide.
Using an unbiased proteomic search, Chen et al. (2008) identified mitochondrial ALDH2 as an enzyme whose activation correlated with reduced ischemic heart damage in rodent models. A high-throughput screen identified a small molecule activator of ALDH2, which they called Alda-1, that, when administered to rats before an ischemic event, reduced infarct size by 60%, most likely through its inhibitory effect on the formation of cytotoxic aldehydes. In vitro, Alda-1 was a particularly effective activator of ALDH2*2 (100650.0001), an inactive mutant form of the enzyme that is found in 40% of East Asian populations. Chen et al. (2008) concluded that the pharmacologic enhancement of ALDH2 activity may be useful for patients with wildtype or mutant ALDH2 who are subjected to cardiac ischemia, such as during coronary bypass surgery.
Hsu et al. (1988) determined that the ALDH2 gene contains at least 13 exons and spans approximately 44 kb.
Hsu et al. (1985) assigned the ALDH2 locus to chromosome 12 by means of a cDNA probe and Southern blot analysis of somatic cell hybrids. With a cDNA fragment corresponding to the 3-prime coding part of human ALDH1 mRNA, Braun et al. (1986) studied human-rodent somatic cell hybrids and confirmed the assignment to chromosome 12. The mitochondrial and cytosolic forms of ALDH are coded by mouse chromosomes 4 and 19, respectively (Mather and Holmes, 1984). Comparative mapping in man, mouse, and bovine led Womack (1990) to suggest that ALDH2 is in the distal part of 12q, distal to IFNG (147570), a conclusion consistent with other information on the mapping of these 2 loci.
Stumpf (2021) mapped the ALDH2 gene to chromosome 12q24.12 based on an alignment of the ALDH2 sequence (GenBank BC071839) with the genomic sequence (GRCh38).
Data on gene frequencies of allelic variants were tabulated by Roychoudhury and Nei (1988).
The ALDH2 alleles encoding the active and inactive subunits are termed 'ALDH2*1' and 'ALDH2*2,' respectively; see 100650.0001. It had been thought that the 2 alleles were expressed codominantly, and that only individuals homozygous for ALDH2*2 were ALDH2-deficient. However, studies of the inheritance of alcohol-induced flushing (610251) in families suggested that the trait is dominant (Schwitters et al., 1982).
Early Studies of ALDH Isoforms
Harada et al. (1980) presented evidence that ALDH is polymorphic in Japanese. They identified 2 major isozymes: a faster migrating (low Km for acetaldehyde) and a slower migrating isozyme (high Km for acetaldehyde). The unusual slower-migrating phenotype, which had less enzymatic activity, was found in 52% of the specimens; the fast-migrating isozyme was absent in these specimens. Harada et al. (1980) postulated that initial intoxicating symptoms after alcohol drinking in these individuals may be due to delayed oxidation of acetaldehyde due to variant or absent ALDH. The slow-migrating ALDH isoform was strongly inactivated by disulfiram, whereas the faster-migrating isoform was relatively insensitive to disulfiram. These isoforms were later identified as ALDH1 and ALDH2, respectively.
Agarwal et al. (1981) performed a population genetic study in East Asians of several different extractions using hair root lysates to investigate ALDH isozymes. Between 40 and 80% of the several East Asian groups were found to be deficient in the faster migrating isozyme, termed ALDH2, whereas not a single European individual was deficient. The deficiency was invariably associated with sensitivity to alcohol. Family studies suggested autosomal recessive inheritance of the deficiency. Harada et al. (1981) found deficiency of the fast-metabolizing isoform in 43% of Japanese; all deficient persons had flushing symptoms and, after alcohol drinking, showed an increased mean acetaldehyde concentration of 37.3 micromoles as compared with 2.1 micromoles in nondeficient persons. Impraim et al. (1982) investigated the basis of the lack in about 50% of East Asians of 1 of the 2 major liver ALDH isozymes. Consistent with a convention of nomenclature adopted by the worldwide workshops, ALDH1 is cytosolic and ALDH2 is mitochondrial. Impraim et al. (1982) confirmed that it was the ALDH2 isozyme that was missing in persons of Asian descent. The unusual ALDH2 isozyme in Japanese liver was enzymatically inactive but immunologically cross-reactive. Thus, a structural mutation at the ALDH2 locus was presumed to be the genetic basis.
Goedde et al. (1983) noted the existence of 4 isozymes of ALDH, which differed in electrophoretic mobility and isoelectric point. In a population study, they found that the frequency of deficiency of the more active isoform was 69% in Indians of the Ecuador Highlands, 44% in Japanese, and 35% in Chinese. This deficiency was not seen in Egyptians, Liberians, Kenyans, or Europeans. The authors suggested that deficiency is related to flushing and a slower metabolism of acetaldehyde, which could in turn result in a lower frequency of alcoholism and alcohol-related problems. (Note that the nomenclature used by some of these authors is confused: ALDH1 is actually ALDH2).
Molecular Basis
Hsu et al. (1987) developed a method for distinguishing the 2 main alleles by means of allele-specific 21-base synthetic oligonucleotides. Using a pair of synthetic oligonucleotides, one complementary to the ALDH2*1 allele and the other complementary to the ALDH2*2 allele,
Shibuya and Yoshida (1988) determined the genotypes of 49 unrelated Japanese persons and 12 Caucasians. The frequency of the atypical allele was found to be 0.35 in the Japanese samples examined. The atypical allele was not found in the Caucasians.
Crabb et al. (1989) did genotyping on the liver from 24 Japanese individuals, using the PCR technique for amplification of genomic DNA. In correlating genotype with phenotype, they found that both heterozygotes and homozygotes for ALDH2*2 are deficient in ALDH2 activity; that is, the ALDH2*2 allele is dominant. Since ALDH2 is a homotetrameric enzyme, random association of active and inactive subunits, equally expressed, should generate about 6% normal tetramers; the remainder would contain at least 1 mutant subunit. Thus, if all tetramers containing at least 1 mutant subunit were inactive, there would be only 6% activity in heterozygotes. This low amount of activity is likely to be below the detection limit of activity staining of the gels.
Using allele-specific oligonucleotides for ALDH2*2, Singh et al. (1989) studied phenotypically deficient individuals in the Chinese, Japanese, and South Korean families to determine heterozygous or homozygous status. All individuals with a heterozygous genotype were found to be deficient, thus demonstrating that only the normal homotetrameric enzyme is catalytically active.
Oota et al. (2004) used the ALDH2*2 allele, which is responsible for catalytic deficiency of ALDH2, and 4 noncoding SNPs to study ALDH2 haplotype frequency and linkage disequilibrium in 37 worldwide populations. Only 4 major SNP-defined haplotypes were found to account for almost all chromosomes in all populations. A fifth haplotype harbored the functional variant and was found only in East Asians.
ALDH2 and Alcoholism
Crabb (1990) pointed out that the single base mutation in ALDH2 responsible for acute alcohol-flushing reaction in Asians, glu504-to-lys (ALDH2*2; 100650.0001), is the best-characterized genetic factor influencing alcohol drinking behavior.
Shibuya et al. (1988) studied 23 Japanese with alcoholic liver disease. No difference was found in the genotypes at the ADH2 (103720) locus; however, at the ALDH2 locus, 20 of the 23 patients were homozygous for ALDH2*1, only 3 were heterozygous, and none of the patients was homozygous for ALDH2*2. The results were interpreted as indicating that Japanese with the atypical allele are at a much lower risk for alcoholic liver disease, presumably due to their sensitivity to alcohol intoxication.
Thomasson et al. (1991) hypothesized that the polymorphisms of both of the liver enzymes responsible for the oxidative metabolism of ethanol may modify the predisposition to development of alcoholism (103780). Using leukocyte DNA amplified by PCR and allele-specific oligonucleotides in a study of Chinese men living in Taiwan, they demonstrated that alcoholics had significantly lower frequencies not only of ALDH2*2 but also of ADH1B*2 (103720.0001) and ADH1C*1 (see 103730.0002). Goedde et al. (1992) gave extensive population frequency data on ALDH2 as well as on ADH1B. They again showed that the atypical ALDH2 gene (ALDH2*2) is extremely rare in Caucasians, Blacks, Papua New Guineans, Australian Aborigines, and Aurocanians (South Chile), but widely prevalent among East Asians. They cited evidence indicating that individuals possessing the ALDH2*2 allele show alcohol-related sensitivity responses such as facial flushing, are usually not habitual drinkers, and appear to suffer less from alcoholism and alcohol-related liver disease.
Muramatsu et al. (1995) used the PCR/RFLP method to determine the genotypes of the ADH2 and ALDH2 loci of alcoholic and nonalcoholic Chinese living in Shanghai. They found that the alcoholics had significantly lower frequencies of the ADH2*2 and ALDH2*2 alleles than did the nonalcoholics, suggesting the inhibitory effects of these alleles for the development of alcoholism. In the nonalcoholic subjects, ADH2*2 had little, if any, effect, despite the significant effect of the ALDH2*2 allele in decreasing the alcohol consumption of the individual. Taken together, these results were considered consistent with the proposed hypothesis for the development of alcoholism, i.e., drinking behavior is greatly influenced by the individual's genotype of alcohol-metabolizing enzymes and the risk of becoming alcoholic is proportionate with the ethanol consumption of the individual.
To investigate possible interactions among the variant alleles ADH2*2, ADH3*1, and ALDH2*2, Chen et al. (1999) genotyped 340 alcoholic and 545 control Han Chinese living in Taiwan at the ADH2, ADH3, and ALDH2 loci. After the influence of ALDH2*2 was controlled for, multiple logistic regression analysis indicated that allelic variation at ADH3 exerts no significant effect on the risk of alcoholism. Any presumed affect could be accounted for by linkage disequilibrium between ADH3*1 and ADH2*2; the 2 genes are located on 4q22. ALDH2*2 homozygosity, regardless of the ADH2 genotype, was fully protective against alcoholism; no individual showing such homozygosity was found among the alcoholics. Logistic regression analyses of the remaining 6 combinatorial genotypes of the polymorphic ADH2 and ALDH2 loci indicated that individuals carrying 1 or 2 copies of ADH2*2 and a single copy of ALDH2*2 had the lowest risk (odds ratios = 0.04-0.05) for alcoholism, as compared with the ADH2*1/*1 and ALDH2*1/*1 genotypes. The disease risk associated with the ADH2*2/*2-ALDH2*1/*1 genotype appeared to be about half of that associated with the ADH2*1/*2-ALDH2*1/*1 genotype. These results suggested that protection afforded by the ADH2*2 allele may be independent of that afforded by ALDH2*2.
Chai et al. (2005) examined ADH2, ADH3, and ALDH2 polymorphisms in 72 alcoholic and 38 nonalcoholic healthy Korean men. Forty-eight of the alcoholic men had Cloninger type 1 and 24 had Cloninger type 2 alcoholism. The frequency of ADH2*1 (103720.0001) and ADH3*2 (103730.0002) alleles was significantly higher in men with type 2 alcoholism than in men with type 1 alcoholism and in healthy men. The frequency of the ALDH2*1 allele was significantly higher in men with alcohol dependence than in healthy men. Chai et al. (2005) suggested that the genetic characteristics of alcohol metabolism in type 1 alcoholism falls between nonalcoholism and type 2 alcoholism.
Luo et al. (2006) genotyped 16 markers within the ADH gene cluster, 4 markers within the ALDH2 gene, and 38 unlinked ancestry-informative markers in a case-control sample of 801 individuals. Associations between markers and disease were analyzed by a Hardy-Weinberg equilibrium test, a conventional case-control comparison, a structured association analysis, and a novel diplotype trend regression (DTR) analysis. All markers were found to be in Hardy-Weinberg equilibrium in controls, but some markers showed Hardy-Weinberg disequilibrium in cases of alcohol dependence. Genotypes of many markers were associated with alcohol dependence. DTR analysis showed that the ADH5 (103710) genotypes and diplotypes of ADH1A (103700), ADH1B (103720), ADH7 (600086), and ALDH2 were associated with alcohol dependence in European Americans and/or African Americans. The risk-influencing alleles were fine mapped from among the markers studied and were found to coincide with some well known functional variants. They demonstrated that DTR was more powerful than many other conventional association methods. They also found that several ADH genes and the ALDH2 gene were susceptibility loci for alcohol dependence, and the associations were best explained by several independent risk genes.
Although the ALDH2*2 allele is considered to be a genetic deterrent for alcoholism, Muramatsu et al. (1996) found that 80 of 655 Japanese alcoholics had the mutant allele. The authors postulated that these alcoholics had some other factor that overcame the adverse effects of acetaldehydemia and that such a factor might reside in the brain's 'reward system,' in which dopamine plays a crucial role. Muramatsu et al. (1996) studied variation at the DRD4 locus (126452) and found a higher frequency of a 5-repeat allele of the DRD4 receptor 48-bp repeat polymorphism in alcoholics with ALDH2*2 than in 100 other alcoholics and 144 controls. They found that alcoholics with the 5-repeat allele also abused other drugs more often.
ALDH2/HMGIC Fusion Gene
Kazmierczak et al. (1995) found that the ALDH2 gene was a translocation partner of the HMGIC gene (HMGA2; 600698) in a uterine leiomyoma. Fusion genes involving HMGIC are found in pleomorphic adenomas of salivary glands and in a variety of benign mesenchymal tumors.
AMED Syndrome, Digenic
In 10 patients from 8 unrelated Japanese families with AMED syndrome (AMEDS; 619151), Oka et al. (2020) identified homozygous or compound heterozygous mutations in the ADH5 gene (103710.0001-103710.0003) as well as a homozygous (3 cases) or heterozygous (7 cases) E504K variant (rs671; 100650.0001) in the ALDH2 gene. The mutations, which were found by whole-exome sequencing (ADH5) or direct sequencing (ALDH2), segregated with the disorder in the families from whom parental DNA was available. Patient cells showed increased sensitivity to formaldehyde treatment compared to controls. In vitro functional expression studies in U2OS cells showed that while loss of either ADH5 or ALDH2 attenuated cell cycle progression, loss of both genes led to significant inhibition of DNA replication after formaldehyde treatment. Patient-derived AMEDS cells showed significant DNA damage after formaldehyde exposure, which could be completely rescued by ectopic expression of either wildtype ADH5 or ALDH2, suggesting that both genes are involved in formaldehyde detoxification. CD34+ hematopoietic progenitor stem cells with loss of ADH5 combined with the ALDH2 variant had impaired proliferation and differentiation capacity, suggesting that formaldehyde detoxification deficiency can cause a wide range of hematopoietic abnormalities. Loss of Adh5 function in combination with reduced Aldh2 activity recapitulated the phenotype of AMEDS in mice. Oka et al. (2020) emphasized that AMEDS is a true digenic disorder, since variations in 2 distinct genes (ADH5 and ALDH2) are necessary and sufficient to cause the disease. Although the ALDH2 variant influences the severity of the disease, it is still essential for disease development. The findings suggested a mechanism in which defects in the enzymatic detoxification processes of highly reactive genotoxic chemicals, such as formaldehyde, results in the accumulation of DNA damage that overburdens DNA repair pathways, thus causing multisystemic effects.
Using an antisense oligonucleotide (ASO-9) containing the 5-prime-TCCC-3-prime motif, which acts by greatly reducing mRNA levels, Garver et al. (2001) showed that rat hepatoma cells had reduced Aldh2 mRNA levels and activity, resulting in more than 90% inhibition of Aldh2 synthesis, probably mediated by RNase H hydrolysis. Mismatches in the TCCC motif, in particular, reduced the efficacy of ASO-9, which specifically reduced mRNA levels of Aldh2 but not of a control mitochondrial enzyme, glutamate dehydrogenase (GLUD1; 138130). Treatment of rats with ASO-9 specifically reduced Aldh2 activity by approximately 40% and increased plasma acetaldehyde levels 4-fold after ethanol administration. Behavioral analysis indicated that ASO-9 treatment induced an aversion to ethanol. After initial consumption, a reduction of 61% in ethanol consumption was observed in treated rats, a level comparable to that achieved with disulfiram (Antabuse). Garver et al. (2001) concluded that the specificity and lack of side effects of an ASO that inhibits ALDH2 expression and mimics the Asian phenotype would be advantageous when compared with disulfiram.
Nitroglycerin, or glyceryl trinitrate (GTN), elicits nitric oxide (NO)-based signaling to dilate blood vessels. Chen et al. (2005) found that mitochondrial bioconversion of GTN to NO was absent in mitochondria obtained from Aldh2-null mice. Vasoactivity from alternative nitro(so)vasodilators was unaffected. GTN bioactivity could still be generated in mutant mice and their isolated vascular tissue, but only at substantially higher concentrations of GTN. Chen et al. (2005) concluded that ALDH2 is necessary and sufficient for vasoactivity derived from therapeutic levels of GTN.
Yao et al. (2010) found that a selective ALDH2 inhibitor (CVT-10216), suppressed cocaine self-administration in rats and prevented cocaine- or cue-induced reinstatement in a rat model of cocaine relapse-like behavior. Inhibition of ALDH2 was found to decrease cocaine-stimulated dopamine production in neurons in the primary ventral tegmental area by increasing the formation of tetrahydropapaveroline (THP). THP was found to selectively inhibit phosphorylated (activated) tyrosine hydroxylase (TH; 191290), and thus reduce dopamine production via negative feedback. Yao et al. (2010) concluded that reducing cocaine- and craving-associated increases in dopamine release appears to be the mechanism by which ALDH2 inhibition suppresses cocaine-seeking behavior.
Langevin et al. (2011) found that the Fanconi anemia DNA repair pathway counteracts acetaldehyde-induced genotoxicity in mice. Their results showed that the acetaldehyde-catabolizing enzyme Aldh2 is essential for the development of Fancd2 (613984)-null embryos. Nevertheless, acetaldehyde-catabolism-competent mothers (Aldh2 heterozygotes) could support the development of double-mutant Aldh2-null/Fancd2-null mice. However, these embryos were unusually sensitive to ethanol exposure in utero, and ethanol consumption by postnatal double-deficient mice rapidly precipitated bone marrow failure. Lastly, Aldh2-null/Fancd2-null mice spontaneously developed acute leukemia. Langevin et al. (2011) concluded that acetaldehyde-mediated DNA damage may critically contribute to the genesis of fetal alcohol syndrome in fetuses, as well to normal development, hematopoietic failure, and cancer predisposition in Fanconi anemia (see 227650) patients.
Garaycoechea et al. (2012) reported that aged Aldh2-null/Fancd2-null mutant mice that do not develop leukemia spontaneously develop aplastic anemia, with the concomitant accumulation of damaged DNA within the hematopoietic stem and progenitor cell (HSPC) pool. Unexpectedly, they found that only HSPCs, and not more mature blood precursors, require Aldh2 for protection against acetaldehyde toxicity. Additionally, the aldehyde-oxidizing activity of HSPCs, as measured by Aldefluor stain, is due to Aldh2 and correlates with this protection. Finally, there is more than a 600-fold reduction in the HSC pool of mice deficient in boh Fanconi anemia pathway-mediated DNA repair and acetaldehyde detoxification. Therefore, Garaycoechea et al. (2012) concluded that the emergence of bone marrow failure in Fanconi anemia is probably due to aldehyde-mediated genotoxicity restricted to the HSPC pool.
The designation for the ALDH2*2 polymorphism has been changed from GLU487LYS to GLU504LYS. The numbering change includes the N-terminal mitochondrial leader peptide of 17 amino acids (Li et al., 2006).
The ALDH2*2-encoded protein was first reported to have a change from glutamic acid (glutamate) to lysine at residue 487 (Yoshida et al., 1984). Hempel et al. (1985) and Hsu et al. (1985) also showed that the catalytic deficiency in mitochondrial ALDH in East Asians that manifests as acute alcohol sensitivity (610251) can be traced to a structural point mutation at amino acid position 487 of the polypeptide. The substitution of lysine for glutamic acid results from a G-A transition.
Alcohol Sensitivity and Protection Against Alcohol Dependence
About 50% of East Asians are missing the ALDH2 isozyme. Impraim et al. (1982) found that the livers of East Asians lacking the ALDH2 isozyme show an enzymatically inactive but immunologically cross-reactive material (CRM) corresponding to the ALDH2 isozyme.
To study the mechanism by which the ALDH2*2 allele exerts its dominant effect in decreasing ALDH2 activity in liver extracts and producing cutaneous flushing when the subject drinks alcohol, Xiao et al. (1995) cloned ALDH2*1 cDNA and generated the ALDH2*2 allele by site-directed mutagenesis. These cDNAs were transduced using retroviral vectors into HeLa and CV1 cells, which do not express ALDH2. The normal allele directed synthesis of immunoreactive ALDH2 protein with the expected isoelectric point and increased aldehyde dehydrogenase activity. The ALDH2*2 allele directed synthesis of mRNA and immunoreactive protein, but the protein lacked enzymatic activity. When ALDH2*1-expressing cells were transduced with ALDH2*2 vectors, both mRNAs were expressed and immunoreactive proteins with isoelectric points ranging between those of the 2 gene products were present, indicating that the subunits formed heteromers. ALDH2 activity in these cells was reduced below that of the parental ALDH2*1-expressing cells. Thus, the authors concluded that ALDH2*2 allele is sufficient to cause ALDH2 deficiency in vitro.
Xiao et al. (1996) referred to the ALDH2 enzyme encoded by the ALDH2*1 allele (the wildtype form) as ALDH2E and the enzyme subunit encoded by ALDH2*2 as ALDH2K. They found that the ALDH2E enzyme was very stable, with a half-life of at least 22 hours. ALDH2K, on the other hand, had an enzyme half-life of only 14 hours. In cells expressing both subunits, most of the subunits assemble as heterotetramers, and these enzymes had a half-life of 13 hours. Thus, the effect of ALDH2K on enzyme turnover is dominant. Their studies indicated that ALDH2*2 exerts its dominant effect both by interfering with the catalytic activity of the enzyme and by increasing its turnover.
Because genetic epidemiologic studies have suggested a mechanism by which homozygosity for the ALDH2*2 allele inhibits the development of alcoholism (103780) in Asians, Peng et al. (1999) recruited 18 adult Han Chinese men, matched by age, body-mass index, nutritional state, and homozygosity at the ALDH2 gene loci from a population of 273 men. Six individuals were chosen for each of the 3 ALDH2 allotypes, i.e., 2 homozygotes and 1 heterozygote. Following a low dose of ethanol, homozygous ALDH2*2 individuals were found to be strikingly responsive with pronounced cardiovascular hemodynamic effects as well as subjective perception of general discomfort for as long as 2 hours following ingestion.
Among 71 Japanese nondrinkers and 268 drinkers of alcohol, Liu et al. (2005) found that drinkers had a significantly higher frequency of the 504glu allele. Individuals with the 504lys allele had an increased risk of alcohol-induced flushing (odds ratio of 33.0).
In a study of 32 adult Han Chinese male students with no personal or family history of alcoholism, Peng et al. (2007) found that heterozygosity for the ALDH2*2 allele resulted in higher acetaldehyde levels after alcohol ingestion compared to wildtype homozygotes. After ingestion, heterozygotes also had faster heart rates, faster blood flow in the facial and carotid arteries, and more subjective discomfort compared to wildtype homozygotes. Overall, the findings indicated that acetaldehyde, rather than ethanol or acetate, are responsible for observed alcohol sensitivity reactions. Peng et al. (2007) postulated that ALDH2*2 heterozygotes have decreased aversion to the adverse effects of alcohol, and thus increased risk of drinking, compared to those who are homozygous for ALDH2*2.
Among 1,032 Korean individuals, Kim et al. (2008) found that the combination of the ADH1B his48 allele (rs1229984; 103720.0001) and the ALDH2 lys504 allele offered protection against alcoholism. Individuals who carried both susceptibility alleles (arg48 and glu504, respectively) had a significantly increased risk for alcoholism (OR, 91.43; p = 1.4 x 10(-32)). Individuals with 1 protective and 1 susceptibility allele had a lesser increased risk for alcoholism (OR, 11.40; p = 3.5 x 10(-15)) compared to those with both protective alleles. Kim et al. (2008) calculated that alcoholism in the Korean population is 86.5% attributable to the detrimental effect of the ADH1B arg48 and the ALDH2 glu504 alleles.
Susceptibility to Severe Hangover
In a study of 140 men and women of Chinese, Japanese, and Korean heritage, Wall et al. (2000) found that those with ALDH2*2 alleles experienced more severe hangovers (see 610251) and suggested that this may contribute, in part, to protection against the development of excessive or problematic drinking in Asian Americans. Yokoyama et al. (2005) found that inactive heterozygous ALDH2, alcohol flushing, and increased mean corpuscular volume (MCV) were positively associated with hangover susceptibility in Japanese workers, suggesting that acetaldehyde is etiologically linked to the development of hangover.
Susceptibility to Alcohol-Related Esophageal Cancer
In a case-control study with 221 Chinese patients with esophageal cancer and 191 controls, Ding et al. (2010) found that alcohol drinkers with the ALDH2 A allele showed a significantly increased risk of esophageal cancer compared to drinkers with the ALDH2 G/G genotype (OR, 3.08) or compared to nondrinkers with any genotype (OR, 3.05). There was a significantly higher risk of esophageal cancer in those with higher alcohol consumption (OR, 11.93), and a dose-dependent positive effect was observed. Drinkers with high cumulative lifetime consumption (greater than 2.5 kg*year calculated as grams of alcohol consumed per day multiplied by number of years of consumption) carrying both the ALHD2 A allele and the G allele of ADH1B (his48 allele) had an even higher risk of esophageal cancer (OR, 53.15) compared to individuals with the ALDH2 G/G and ADH1B A/A genotypes. Ding et al. (2010) hypothesized that increased acetaldehyde in drinkers with these susceptibility alleles has a carcinogenic effect.
Susceptibility to Poor Response to Sublingual Nitroglycerin
In 80 Han Chinese patients with arteriography-confirmed coronary artery disease who used only sublingual nitroglycerin, or glyceryl trinitrate (GTN) for angina relief, Li et al. (2006) found that the ALDH2*2 allele was associated with lack of efficacy of sublingual GTN. Enzyme kinetic analysis revealed that the catalytic efficiency of GTN metabolism of the glu504 protein is approximately 10-fold higher than that of the lys504 enzyme. Li et al. (2006) concluded that the presence of the ALDH2*2 allele contributes, in large part, to the lack of an efficacious clinical response to GTN and recommended that this genetic factor be considered when administering GTN, particularly to Asian patients, 30 to 50% of whom possess the inactive ALDH2*2 mutant allele.
AMED Syndrome, Digenic
In 10 patients from 8 unrelated Japanese families with AMED syndrome (AMEDS; 619151), Oka et al. (2020) identified homozygous or compound heterozygous mutations in the ADH5 gene (103710.0001-103710.0003) as well as a homozygous (3 cases) or heterozygous (7 cases) E504K variant in the ALDH2 gene. The mutations, which were found by whole-exome sequencing (ADH5) or direct sequencing (ALDH2), segregated with the disorder in the families from whom parental DNA was available. Patient cells showed increased sensitivity to formaldehyde treatment compared to controls. In vitro functional expression studies in U2OS cells showed that while loss of either ADH5 or ALDH2 attenuated cell cycle progression, loss of both genes led to significant inhibition of DNA replication after formaldehyde treatment. Patient-derived AMEDS cells showed significant DNA damage after formaldehyde exposure, which could be completely rescued by ectopic expression of either wildtype ADH5 or ALDH2, suggesting that both genes are involved in formaldehyde detoxification. CD34+ hematopoietic progenitor stem cells with loss of ADH5 combined with the ALDH2 variant had impaired proliferation and differentiation capacity, suggesting that formaldehyde detoxification deficiency can cause a wide range of hematopoietic abnormalities. Loss of Adh5 function in combination with reduced Aldh2 activity recapitulated the phenotype of AMEDS in mice. Oka et al. (2020) emphasized that AMEDS is a true digenic disorder, since variations in 2 distinct genes (ADH5 and ALDH2) are necessary and sufficient to cause the disease. Although the ALDH2 variant influences the severity of the disease, it is still essential for disease development. The findings suggested a mechanism in which defects in the enzymatic detoxification processes of highly reactive genotoxic chemicals, such as formaldehyde, results in the accumulation of DNA damage that overburdens DNA repair pathways, thus causing multisystemic effects.
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