ClinVar Genomic variation as it relates to human health

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. (less)

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. (less)

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. (less)

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. (less)

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. (less)

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. (less)