Alternative titles; symbols
HGNC Approved Gene Symbol: ADH1B
Cytogenetic location: 4q23 Genomic coordinates (GRCh38): 4:99,304,971-99,321,401 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 4q23 | {Aerodigestive tract cancer, squamous cell, alcohol-related, protection against} | 103780 | Multifactorial | 3 |
| {Alcohol dependence, protection against} | 103780 | Multifactorial | 3 |
The ADH1B gene encodes the beta subunit of class I alcohol dehydrogenase (ADH) (EC 1.1.1.1), an enzyme that catalyzes the rate-limiting step for ethanol metabolism: the oxidation of alcohol to acetaldehyde. Class 1 ADH is a homo- or heterodimeric molecule, formed by the association of 3 types of class I ADH subunits, alpha (ADH1A; 103700), beta, and gamma (ADH1C; 103730) (Edenberg, 2007).
For a general discussion of ADH, including evolution of the class I ADH genes, see 103700.
The amino acid numbering system used throughout reflects inclusion of the ATG translation initiation codon in the ADH1B sequence (Edenberg, 2007).
Ikuta et al. (1985) isolated clones corresponding to the ADH beta-1 subunit from a human liver cDNA library, which encoded a deduced 375-amino acid protein. Some sequences were found to be common to the 3 ADH subunits: alpha, beta, and gamma.
Ikuta et al. (1986) isolated clones corresponding to the 3 class I ADH subunits from a human liver cDNA library. The 3 subunits had a very similar amino acid identity (93 to 95% identity), but there were distinctive differences at the zinc-binding cys47 residue, reflecting differences in kinetic properties. Heden et al. (1986) identified cDNA clones coding for the beta subunit of human liver ADH and found that the gene has differently sized 3-prime noncoding regions. Yokoyama et al. (1987) also cloned the gene coding for the beta-1 subunit of human ADH.
See 103700 for evidence on the mapping of the ADH1B gene in the cluster of related genes on chromosome 4q22.
As outlined by Osier et al. (2002), 7 ADH genes are clustered in a region of approximately 380 kb on chromosome 4q21-q23. The class I ADH genes are situated in a tighter cluster of approximately 77 kb, in the following order: ADH1C, ADH1B, and ADH1A. This cluster of class I ADH genes is flanked upstream by ADH7 (600086) and downstream by ADH6 (103735), ADH4 (103740), and ADH5 (103710), in that order. Although the greatest similarity seen is among the class I genes, all 7 ADH enzymes are very similar in amino acid sequence and structure, but differ in preferred substrates (Edenberg, 2000).
According to the conclusion of Smith et al. (1973), ADH1B is expressed in the lung in early fetal life and remains active in this tissue throughout life. It is active also in liver after about the first trimester and gradually increases in activity, such that in adults this locus is responsible for most of the liver ADH activity. The enzyme is also active in the adult kidney.
Data on gene frequencies of allelic variants were tabulated by Roychoudhury and Nei (1988). Goedde et al. (1992) presented extensive data on population frequencies of the ADH2 and ALDH2 (100650) genes.
Von Wartburg and Schurch (1968) described atypical human liver ADH in 2 of 50 English livers and in 12 of 59 Swiss livers. The difference studied concerned the ratio of activity at pH 10.8 and pH 8.8. The results suggested polymorphisms at class I ADH loci. Stamatoyannopoulos et al. (1975) found that 85% of Japanese carry an 'atypical' liver ADH1B isoform, characterized by faster electrophoretic migration. This variant had 6-fold increased ADH activity at pH 8.8 compared to the typical isoform. About the same proportion of Japanese individuals have alcohol sensitivity, which the authors suggested may be due to increased formation of acetaldehyde by persons with the atypical ADH1B. The frequency of the atypical ADH1B isoform was much higher in Japanese compared to Caucasians. Harada et al. (1980) also reported a frequency of 85% for the atypical ADH variant among 40 Japanese autopsy livers.
The amino acid numbering system used below reflects inclusion of the ATG initiation codon in the ADH1A sequence (Edenberg, 2007). Jornvall et al. (1984) and Matsuo et al. (1989) showed that the typical and atypical forms of ADH1B differ by only a single amino acid (R48H; 103720.0001; rs1229984). The ADH1B typical isoform contains arg48, whereas the 'atypical' isoform contains his48. The V(max) of ethanol oxidation to acetaldehyde was increased by 100-fold in homozygotes for the atypical allele compared to homozygotes for the typical allele.
Burnell et al. (1987) demonstrated that in the homozygote for a third ADH1B allele, formerly called beta(Indianapolis) (Bosron et al., 1980), was an arg370-to-cys (R370C; 103720.0002) substitution in the ADH1B gene. The cys370 variant has decreased affinity for the coenzyme NADH, but higher enzyme activity.
Among 9,080 Caucasian Danish men and women, Tolstrup et al. (2008) found that those with genotypes encoding slow alcohol metabolism ADH1B*1 and ADH1C*2 (see 103730.0001) drank more alcohol and had higher risks of alcoholism (103780) compared to those with genotypes encoding faster alcohol metabolism. Effect sizes were smaller for the ADH1C genotype than for the ADH1B genotype. Since slow ADH1B alcohol degradation (arg48) is found in more than 90% of the white population compared to less than 10% of East Asians, the population attributable risk of heavy drinking and alcoholism by the ADH1B arg48/arg48 genotype was 67% and 62% among the white population compared to 9% and 24% among the East Asian population.
ADH1B Variants and ALDH Variants
Harada et al. (1980) reported a frequency of 85% for the atypical ADH variant among 40 Japanese autopsy livers. These individuals also had 2 major isozymes of ALDH (ALDH2; 100650): 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 Japanese specimens. The authors postulated that initial intoxicating symptoms after alcohol drinking in these individuals may be due to delayed oxidation of acetaldehyde due to variant ALDH rather than to the higher-than-normal production by typical or atypical ADH.
Muramatsu et al. (1995) used the PCR/RFLP method to determine the genotypes of the ADH1B and ALDH2 loci of alcoholic and nonalcoholic Chinese living in Shanghai. They found that the alcoholics had significantly lower frequencies of the ADH1B*2 and ALDH2*2 (100650.0001) alleles than did the nonalcoholics, suggesting an inhibitory effect of these alleles for the development of alcoholism or alcohol dependence (103780). In the nonalcoholic subjects, ADH1B*2 had little, if any, effect, despite the significant effect of the ALDH2*2 allele in decreasing the alcohol consumption of the individual. There results were 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 to the ethanol consumption of the individual.
Takeshita et al. (1996) evaluated the effects of the ADH1B polymorphism in 524 Japanese individuals who had previously been typed for the ALDH2 polymorphism. In the ALDH2 heterozygotes, the frequency of facial flushing following consumption of one glass of beer was significantly higher in the presence of the ADH1B*2 allele in homozygous or heterozygous form. The proportion of individuals with ethanol-induced cutaneous erythema was also higher depending on the presence of the ADH1B variant allele in ALDH2*1 homozygotes or ALDH2*1/ALDH2*2 heterozygotes. Takeshita et al. (1996) presented evidence that drinking habits were not significantly associated with the ADH1B genotype.
The variant alleles ADH1B*2 and ADH1C*1 (see 103730.0001 and 103730.0002), which encode high-activity ADH isoforms, and the ALDH2*2 allele, which encodes the low-activity form of ALDH2, protect against alcoholism in East Asians. To investigate possible interactions among these protective genes, Chen et al. (1999) genotyped 340 alcoholic and 545 control Han Chinese living in Taiwan at the ADH1B, ADH1C, and ALDH2 loci. After the influence of ALDH2*2 was controlled for, multiple logistic regression analysis indicated that allelic variation at ADH1C exerted no significant effect on the risk of alcoholism. This could be accounted for by linkage disequilibrium between ADH1C*1 and ADH1B*2. ALDH2*2 homozygosity, regardless of the ADH1B 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 ADH1B and ALDH2 loci indicated that individuals carrying 1 or 2 copies of ADH1B*2 and a single copy of ALDH2*2 had the lowest risk (odds ratios = 0.04-0.05) for alcoholism, as compared with the ADH1B*1/*1 and ALDH2*1/*1 genotypes. The disease risk associated with the ADH1B*2/*2-ALDH2*1/*1 genotype appeared to be about half of that associated with the ADH1B*1/*2-ALDH2*1/*1 genotype. These results suggested that protection afforded by the ADH1B*2 allele may be independent of that afforded by ALDH2*2.
Osier et al. (2002) reported a study into the nature of linkage disequilibrium and genetic variation in the ADH cluster in population samples from different regions of the world. Linkage disequilibrium across approximately 40 kb of the class I ADH cluster was moderate to strong in all population samples studied. Osier et al. (2002) stated that the allelic series for ADH1B is generated by variation at 2 different sites at the genomic level. The ADH1B*1 allele is composed of arg48 and arg370 (R370C; 103720.0002), and the ADH1B*2 allele is composed of his48 and arg370. The ADH1B*3 allele is composed of arg48 and cys370. Osier et al. (2002) stated that the 'double variant' (composed of his48 and cys370) could exist but had not been observed.
The ARG47HIS variant has been designated as R48H based on numbering which includes the translation initiation codon (Edenberg, 2007). The HIS variant is associated with more rapid ethanol oxidation to acetaldehyde compared to the ARG variant.
The arg48 and his48 variants of ADH1B are often referred to as ADH1B*1 and ADH1B*2, respectively. However, Osier et al. (2002) noted that ADH1B*1 and ADH1B*2 are alleles that also include the ADH1B R370C variant (103720.0002).
Jornvall et al. (1984) determined that the 'atypical' variant of ADH1B, commonly found in persons of Asian origin, results from an arg48-to-his (R48H) substitution in exon 3 of the gene, in a position that binds the pyrophosphate group of coenzyme NAD(H); this change explains the functional differences between the 2 isozymes, including both a lower pH optimum and higher turnover of the atypical variant.
Matsuo et al. (1989) also showed that the 'typical' and 'atypical' forms of ADH1B differ by only a single amino acid: R48H, resulting from a G-to-A transition. The ADH1B*1 typical allele has an arg48 (CGC), whereas the ADH1B*2 atypical allele has his48 (CAC). The kinetic properties of the 2 variants in the coenzyme binding site were found to differ considerably: the V(max) of ethanol oxidation to acetaldehyde was increased by 100-fold in homozygotes for the his48 allele compared to homozygotes for the arg48 allele.
Using site-directed mutagenesis, Hurley et al. (1990) studied the effects of substitution of lysine, histidine, glutamine, and glycine for arginine-48 in beta-1/beta-1. They expressed the enzymes in E. coli and compared their kinetics.
Alcohol Dependence, Protection Against
Osier et al. (1999) showed that the arg48-to-his (R48H) site of ADH1B is in linkage disequilibrium with the ADH1C ile350-to-val (I350V; 103730.0002) site, and identified R48H as being responsible for differences in ethanol metabolism and alcoholism among Taiwanese, with the I350V site showing association only because of linkage disequilibrium.
Shea et al. (2001) evaluated 84 Ashkenazi Jewish American college students to determine the prevalence of the ADH1B*2 allele (his48) (0.31). Carriers of the ADH1B*2 allele reported significantly fewer drinking days per month. ADH1B*2 was not related to alcohol use disorders, alcohol-induced flushing and associated symptoms, number of binge drinking episodes in the previous 90 days, maximum number of drinks ever consumed, or self-reported levels of response to alcohol. The results suggested that Ashkenazi Jewish Americans with ADH1B*2 alleles drink less frequently, which may contribute to the overall lower rates of alcohol dependence (103780) in this population.
Carr et al. (2002) studied the ADH1B polymorphisms in 4 groups of Jewish subjects (males and females in college age and general populations) to determine whether there was an association between the ADH1B*2 allele, which has a higher frequency in Jewish than in other Caucasian groups, and alcohol consumption. Both groups of men with the ADH1B*2 allele reported more unpleasant reactions following alcohol consumption. Men in the general population with the ADH1B*2 allele drank alcohol less frequently; there was a similar trend among women. The college students consumed considerably more alcohol than the general population, suggesting that social setting and age have a stronger influence on alcohol drinking than the ADH1B*2 effect.
Whitfield (2002) commented on differences in the effects of the R47H mutation between Europeans and 2 major east Asian populations, Chinese and Japanese, and offered explanations. Kidd et al. (2002) disagreed with some of the conclusions of Whitfield (2002) and offered other explanations.
Suzuki et al. (2004) found an association between the ADH1B*1 allele and increased risk of lacunae and cerebral infarction in a cohort of over 1,000 Japanese men. The association was not seen in women.
Chai et al. (2005) examined ADH1B, ADH1C (103730), and ALDH2 (100650) 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 (see 103780). The frequency of ADH1B*1 and ADH1C*2 (see 103730.0001) 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 (100650.0001) 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 I alcoholism fall between nonalcoholism and type II alcoholism.
Because the common belief that selection has operated on the ADH1B his48 allele in East Asian populations lacks direct biologic or statistical evidence, Han et al. (2007) used genomic data to test the hypothesis. Data consisted of 54 SNPs across the ADH clusters in a global sampling of 42 populations. Both the F(st) statistic and the long-range haplotype (LRH) test provided positive evidence of selection in several East Asian populations. The ADH1B R48H functional polymorphism had the highest F(st) of the 54 SNPs in the ADH cluster, and it was significantly above the mean F(st) of 382 presumably neutral sites tested on the same 42 population samples. The LRH test that used cores including that site and extending on both sides also gave significant evidence of positive selection in some East Asian populations for a specific haplotype carrying the ADH1B his48 allele. Interestingly, this haplotype is present in high frequency in only some East Asian populations, whereas the specific allele also exists in other East Asian populations and in the Near East and Europe but does not show evidence of selection with use of the LRH test. Although the ADH1B his48 allele conveys a well-confirmed protection against alcoholism, that modern phenotypic manifestation does not easily translate into a positive selective force, and the nature of that selective force remained speculative.
The ADH1B R48H polymorphism (rs1229984) is the SNP generally regarded as the most important with respect to alcoholism (or alcoholism protection) in the ADH gene family in Asia. The his48 frequency is particularly high in eastern Asian populations, often exceeding 80%, but the allele is almost absent in sub-Saharan, European, and Native American populations. The high frequency of the derived allele in Asia could have resulted from either of 2 possible evolutionary processes: (1) a selective advantage existing only in eastern Asia for the allele, or (2) random genetic drift increasing the frequency of the allele in eastern Asia. Li et al. (2007) pointed to the high frequency of the his48 allele not only in eastern Asian populations but also in southwestern Asia and in populations deriving from southwestern Asia. In a metaanalysis, Li et al. (2007) reported new frequency data confirming the observation that there is a low frequency of this allele in the region between eastern and western Asia. In western Asia, the highest frequencies were found in the Persians, Turks, Samaritans, and Jewish individuals from a variety of regions. The distribution suggested that the derived allele increased in frequency independently in western and eastern Asia after humans had spread across Eurasia.
Among 9,080 Caucasian Danish men and women, Tolstrup et al. (2008) found that men and women homozygous for the slower metabolizing arg48 allele had a higher alcohol intake compared to those with the his48 allele. Individuals with the arg48 allele also had higher rates of alcoholism and alcohol-related hospitalizations.
Among 1,032 Korean individuals, Kim et al. (2008) found that the combination of the ADH1B his48 allele and the ALDH2 lys504 allele (100650.0001) 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.
Borinskaya et al. (2009) presented population frequencies for central Asia and Siberia that differed slightly from previous reports, particularly that of Li et al. (2007). Borinskaya et al. (2009) found a mean frequency of 4.9% among 1,019 Russian individuals, and 20.4% among the southern Turkmen near northern Iran, both lower than reported by Li et al. (2007). The overall allele frequencies of 3,408 individuals in 46 additional populations from southwest Asia was closer to those in central Asia (19% to 32%), suggesting a less pronounced discontinuity between west and east Asia. Borinskaya et al. (2009) presented a refined geographic map of the distribution of the R48H allele including 172 populations from Africa and Eurasia. The southwest Asian local maximum reaches 30% frequency and is connected with the southeast Asian maximum via the Asian steppe belt, where the average allele frequency is 20 to 30%. The frequency from the steppe region toward the North and West declines gradually to 10 to 16% in populations across the Caucasus and Volga-Ural regions, with the exception of the Kalmyk population (26.3%), who have ancestor roots from Mongol-Oirat tribes who migrated from central Asia approximately 300 years ago. In a response, Li and Kidd (2009) agreed that there is a more continuous low-frequency distribution of the his48 allele across central Asia. However, haplotype analysis suggested that the his48 allele occurred on 2 haplotypes in western Asia that were not seen in eastern Asia. They presented additional frequencies for western Asia, and noted that the frequency is always higher in Jewish populations from Africa, Europe, and the Middle East (26 to 41%) and the Druze population (27%) than in Arab populations (9.5 to 15.7%). The population frequency of his48, which has now reached over 300 different populations, continues to be collected and deposited in an online resource (ALFRED).
Macgregor et al. (2009) tested for associations between 9 polymorphisms in the ALDH2 gene and 41 in the ADH genes, and alcohol-related flushing, alcohol use, and dependence symptom scores in 4,597 Australian twins, predominantly of European ancestry. The vast majority (4,296 individuals) had consumed alcohol in the previous year, with 547 meeting DSM-IIIR criteria for alcohol dependence. There were study-wide significant associations between rs1229984 and flushing and consumption, but only nominally significant associations (p less than 0.01) with alcohol dependence. Individuals carrying the G allele/arg48 reported a lower prevalence of flushing after alcohol, consumed alcohol on more occasions, had a higher maximum number of alcoholic drinks in a single day and a higher overall alcohol consumption in the previous year than those with the less common A allele/his48. After controlling for rs1229984, an independent association was observed between rs1042026 in the ADH1B gene and alcohol intake and suggestive associations between alcohol consumption phenotypes and rs1693482 in the ADH1C gene (see 103730.0001), rs1230165 (ADH5; 103710) and rs3762894 (ADH4; 103740). ALDH2 variation was not associated with flushing or alcohol consumption, but was weakly associated with alcohol dependence measures. These results bridge the gap between DNA sequence variation and alcohol-related behavior, confirming that the ADH1B R48H polymorphism affects both alcohol-related flushing in Europeans and alcohol intake.
Alcohol-Related Aerodigestive Tract Cancer, Protection Against
Cancers of the upper aerodigestive tract, comprising the oral cavity, pharynx, larynx, and esophagus, are common cancers. Taken together, they account for 5.2% of all cancer cases worldwide. Tobacco and alcohol represent important risk factors for these cancers, with evidence of a synergistic interaction. The mechanism for alcohol drinking as a risk factor of upper aerodigestive tract cancers is unclear: it may act as a solvent for tobacco carcinogens, or it is also possible that acetaldehyde, the metabolite of ethanol, is the primary carcinogen (Hashibe et al., 2006). Hashibe et al. (2008) genotyped 6 genetic variants of the alcohol dehydrogenase genes (ADH) in 3 cohorts from Europe and Latin America, including an expanded central European study group previously reported by Hashibe et al. (2006). The total study population comprised 3,876 patients with squamous cell cancer of the aerodigestive tract, including 1,790 cancers of the oral cavity or pharynx, 1,659 of the hypopharynx or larynx, and 427 cancers of the esophagus, and 5,278 controls. A significant protective effect was observed for rs1229984 in the ADH1B gene (R48H) with a combined p value of 8.0 x 10(-10) and for rs1573496 in the ADH7 gene (600086) with a combined p value of 3.0 x 10(-9). Although both the ADH1B and ADH7 genes map to the same cluster on chromosome 4q22, there was no evidence of linkage disequilibrium between these 2 variants, indicating independent effects. Stratification by cancer type showed heterogeneity: the highest protection offered by the ADH1B R48H was against laryngeal cancer, whereas the highest protection offered by the ADH7 SNP was against esophageal cancer (133239). For both variants, there was an increasing protective effect with increasing alcohol consumption (103780); in fact there was no protective effect in never-drinkers for either variant. The data suggested that the protective effects of these gene-environment interactions was due to their role in changing the carcinogenic effects of alcohol.
The ARG369CYS variant has been designated as R370C (rs2066702) based on numbering which includes the translation initiation codon (Edenberg, 2007).
The cys369 variant of ADH1B is often referred to as ADH1B*3. However, Edenberg (2007) noted that ADH1B*3 is an allele that also includes the arg48 ADH1B variant (103720.0001).
Bosron et al. (1980) described a novel molecular isoform of human ADH1B, designated ADH(Indianapolis), in 29% of liver specimens from African Americans. Bosron et al. (1983) found that the frequency of the Indianapolis variant was 0.16 in African Americans and was not found in any of 63 livers from white Americans. Agarwal et al. (1981) could find no instance of the Indianapolis variant in Germany or Japan.
Burnell et al. (1987) demonstrated that the variant observed in African Americans results from an arg370-to-cys substitution in exon 9 of the ADH1B gene: they referred to this variant as ADH1B*3. Burnell et al. (1987) predicted that arg370 interacts with the nicotinamide phosphate moiety of NAD(H) and that this accounts for the effect of the R370C substitution in decreasing the isoenzyme's affinity for coenzyme, which results in higher turnover rate during ethanol oxidation.
Edenberg et al. (2006) presented evidence suggesting that the ADH1B*3 allele has a protective effect against alcohol dependence (see 103780) among African Americans.
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