Alternative titles; symbols
HGNC Approved Gene Symbol: ADH1C
Cytogenetic location: 4q23 Genomic coordinates (GRCh38): 4:99,336,497-99,352,746 (from NCBI)
Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
---|---|---|---|---|
4q23 | {Alcohol dependence, protection against} | 103780 | Multifactorial | 3 |
{Parkinson disease, susceptibility to} | 168600 | Autosomal dominant; Multifactorial | 3 |
The ADH1C gene encodes the gamma 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 (ADH1B; 103720), and gamma (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 ADH1C sequence (Edenberg, 2007).
Ikuta et al. (1986) isolated clones corresponding to the ADH1C gene from a human liver cDNA library. The deduced 375-amino acid protein was almost identical to the proposed sequence of the gamma-1 subunit as described by Buhler et al. (1984), with ile350. The gamma-1 and gamma-2 homozygotes showed similar enzymatic properties. However, they differ in NADH dissociation.
Hoog et al. (1986) determined the cDNA and amino acid structures of the gamma-1 and gamma-2 isoforms of human liver ADH. They found that gamma-1 had arg272 and ile350, whereas gamma-2 had gln272 and val350 (R272G, 103730.0001; I350V, 103730.0002, respectively). The val277-to-met variant previously reported by Ikuta et al., 1986 was considered to be unreliable due to enzymatic cleavage patterns. Hoog et al. (1986) concluded that I350V was not important for enzymatic properties of the enzyme given its location, and suggested that R272G variation was important for total charge and catalytic properties as well as NADH coenzyme interaction.
Xu et al. (1988) concluded that the gamma-1 and gamma-2 isoforms can be distinguished by ile or val at position 350, respectively.
Xu et al. (1988) determined that the ADH1C gene contains 8 exons.
Zgombic-Knight et al. (1997) characterized the mouse Adh3 gene, which consists of 9 exons spanning approximately 14 kb.
See 103700 for evidence on the mapping of the human ADH1C gene to the cluster of related genes on chromosome 4q22.
Holmes (1979) mapped the mouse Adh3 gene to chromosome 3.
According to the conclusion of Smith et al. (1973), the ADH1C gene is active in intestine and kidney in fetal and early postnatal life, and persists in the stomach and liver in adult life. The authors identified 2 different common isoforms, termed gamma-1 and gamma-2, that differed in electrophoretic pattern. The gamma-2 homozygote appeared to have weaker activity compared to the gamma-1 homozygote.
Two alleles at the ADH1C locus, called gamma-1 and gamma-2, have a frequency of about 0.63 and 0.37, respectively (Smith et al., 1973). Data on gene frequencies of allelic variants were tabulated by Roychoudhury and Nei (1988). The gamma-1 allele, now known as ADH1C*1, was defined as a gamma subunit that has arg272 and ile350 (Hoog et al., 1986). In almost all cases, these 2 SNPs are in linkage disequilibrium with one another. The gamma-2 allele, now known as ADH1C*2, has gln272 and val350.
In epidemiologic studies, moderate consumption of alcohol had been consistently associated with a reduced risk of myocardial infarction; however, the mechanism underlying this association was unclear. Hines et al. (2001) evaluated the hypothesis that the effect of moderate alcohol consumption on the risk of myocardial infarction would vary according to the ADH3 genotype. They found that as compared with homozygosity for the allele associated with a fast rate of ethanol oxidation (gamma-1), homozygosity for the allele associated with a slow rate of ethanol oxidation (gamma-2) was associated with a reduced risk of myocardial infarction. Men who had consumed at least one drink per day and were homozygous for the gamma-2 allele had the greatest reduction in risk; such men also had the highest plasma HDL levels. Hines et al. (2001) confirmed the interaction among the ADH3 genotype, the level of alcohol consumption, and the HDL level in an independent study of postmenopausal women.
In DNA extracts from individuals belonging to a Southwest American Indian tribe with a high prevalence of alcoholism, Mulligan et al. (2003) assayed variants at the ADH2, ADH3, and ALDH2 (100650) loci. Both linkage and association analysis identified several ADH3 alleles and a neighboring microsatellite marker that affected risk of alcohol dependence and were also related to binge drinking.
Buervenich et al. (2005) found an association between a truncating polymorphism in the ADH3 gene (G78X; 103730.0003) and the development of Parkinson disease (168600).
The ARG271GLN variant has been designated as R272Q based on numbering which includes the translation initiation codon (Edenberg, 2007).
Hoog et al. (1986) found 2 amino acid differences between the gamma-1 and gamma-2 alleles: an arg272-to-gln (rs1693482) substitution in exon 6 and an ile350-to-val (I350V; 103730.0002) substitution in exon 8 of the ADH1C gene. They determined that the R272Q substitution was responsible for the differences in enzymatic properties, whereas the I350V substitution had no special importance. The location of R272Q appeared important for total charge and catalytic properties, as well as NADH coenzyme interaction.
The gamma-1 allele, now known as ADH1C*1, was originally defined as a gamma subunit that has arg272 and ile350 (Hoog et al., 1986). In almost all cases, these 2 SNPs are in linkage disequilibrium with one another. The gamma-2 allele, now known as ADH1C*2, has gln272 and val350. Homozygosity for the ADH1C*1 allele has a 70% higher turnover rate than homozygosity for ADH1C*2 allele (Edenberg, 2007).
Chai et al. (2005) examined ADH1B, ADH1C, and ALDH2 polymorphisms in 72 alcoholic and 38 nonalcoholic healthy Korean men; 48 patients had type I alcoholism, and 24 had type II alcoholism. The frequency of ADH1B*1 (103720.0001) and ADH1C*2 alleles was significantly higher in men with type II alcoholism than in men with type I alcoholism and in healthy men. The frequency of the ALDH2*1 (100650.0001) allele was significantly higher in men with alcohol dependence (103780) 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.
Among 9,080 Caucasian Danish men and women using the Michigan Alcohol Screening Test, Tolstrup et al. (2008) found that men heterozygous or homozygous for the slower metabolizing ADH1C*2 allele had a 40 to 70% higher risk for heavy or excessive alcohol intake compared to those homozygous for the fast metabolizing ADH1C*1 allele. Similar results were found for women, but effect sizes were smaller and reached significance only for heavy drinking.
The ILE349VAL variant has been designated as I350V based on numbering which includes the translation initiation codon (Edenberg, 2007).
Hoog et al. (1986) found 2 amino acid differences between the gamma-1 and gamma-2 alleles: an arg271-to-gln (R271Q; 103730.0001) substitution in exon 6 and an ile349-to-val (rs698) substitution in exon 8 of the ADH1C gene. They determined that the R272Q substitution was responsible for the differences in enzymatic properties, whereas the I350V substitution had no special importance. The location of R272Q appeared important for total charge and catalytic properties, as well as NADH coenzyme interaction.
The gamma-1 allele, now known as ADH1C*1, was originally defined as a gamma subunit that has arg272 and ile350 (Hoog et al., 1986). In almost all cases, these 2 SNPs are in linkage disequilibrium with one another. The gamma-2 allele, now known as ADH1C*2, has gln272 and val350. Homozygosity for the ADH1C*1 allele has a 70% higher turnover rate than homozygosity for ADH1C*2 allele (Edenberg, 2007).
Xu et al. (1988) used the I350V substitution to distinguish ADH1C*1 from ADH1C*2 by means of allele-specific oligonucleotide probes.
Osier et al. (1999) showed that I350V substitution is in linkage disequilibrium with the ADH1B arg48-to-his (R48H; 103720.0001) substitution, and identified the R48H variant as being responsible for differences in ethanol metabolism and alcoholism (103780) among Taiwanese, with the I350V variant showing association only because of linkage disequilibrium.
Chai et al. (2005) examined ADH1B, ADH1C, and ALDH2 polymorphisms in 72 alcoholic and 38 nonalcoholic healthy Korean men; 48 patients had type I alcoholism, and 24 had type II alcoholism. The frequency of ADH1B*1 (103720.0001) and ADH1C*2 alleles was significantly higher in men with type II alcoholism (103780) than in men with type I 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.
Among 9,080 Caucasian Danish men and women using the Michigan Alcohol Screening Test, Tolstrup et al. (2008) found that men heterozygous or homozygous for the slower metabolizing ADH1C*2 allele had a 40 to 70% higher risk for heavy or excessive alcohol intake compared to those homozygous for the fast metabolizing ADH1C*1 allele. Similar results were found for women, but effect sizes were smaller and reached significance only for heavy drinking.
Buervenich et al. (2005) found an association between a G-to-T transversion in exon 3 of the ADH1C gene (rs283413), resulting in a gly78-to-ter (G78X) polymorphism, and the development of Parkinson disease (168600). The G78X substitution was found in 22 (2%) of 1,076 PD patients of European ancestry and 6 (0.6%) of 940 controls, which was statistically significant and conferred an odds ratio of 3.25 for development of the disease. In addition, the G78X variant was identified in 4 (10%) of 40 Caucasian index PD patients, 3 of whom had a family history of the disorder. Buervenich et al. (2005) noted that ADH1C plays a role in detoxification, and suggested that defects in this enzyme may render some individuals more susceptible to environmental toxins, which may contribute to the development of PD.
Azevedo, E. S., Da Silva, M. C. B. O., Tavares-Neto, J. Human alcohol dehydrogenase ADH 1, ADH 2 and ADH 3 loci in a mixed population of Bahia, Brazil. Ann. Hum. Genet. 39: 321-327, 1976. [PubMed: 1275443] [Full Text: https://doi.org/10.1111/j.1469-1809.1976.tb00136.x]
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Holmes, R. S. Genetics and ontogeny of alcohol dehydrogenase isozymes in the mouse: evidence for a cis-acting regulator gene (Adt-I) controlling C(2) isozyme expression in reproductive tissues and close linkage of Adh-3 and Adt-I on chromosome 3. Biochem. Genet. 17: 461-472, 1979. [PubMed: 518534] [Full Text: https://doi.org/10.1007/BF00498884]
Hoog, J.-O., Heden, L.-O., Larsson, K., Jornvall, H., von Bahr-Lindstrom, H. The gamma-1 and gamma-2 subunits of human liver alcohol dehydrogenase: cDNA structures, two amino acid replacements, and compatibility with changes in the enzymatic properties. Europ. J. Biochem. 159: 215-218, 1986. [PubMed: 3758060] [Full Text: https://doi.org/10.1111/j.1432-1033.1986.tb09855.x]
Ikuta, T., Szeto, S., Yoshida, A. Three human alcohol dehydrogenase subunits: cDNA structure and molecular and evolutionary divergence. Proc. Nat. Acad. Sci. 83: 634-638, 1986. [PubMed: 2935875] [Full Text: https://doi.org/10.1073/pnas.83.3.634]
Morris, D. J., Willem, P., dos Santos, M., Povey, S., Jenkins, T. A new chromosome 4q marker, D4S138, closely linked to the ADH3 locus. (Abstract) Cytogenet. Cell Genet. 51: 1047-1048, 1989.
Mulligan, C. J., Robin, R. W., Osier, M. V., Sambuughin, N., Goldfarb, L. G., Kittles, R. A., Hesselbrock, D., Goldman, D., Long, J. C. Allelic variation at alcohol metabolism genes (ADH1B, ADH1C, ALDH2) and alcohol dependence in an American Indian population. Hum. Genet. 113: 325-336, 2003. [PubMed: 12884000] [Full Text: https://doi.org/10.1007/s00439-003-0971-z]
Osier, M., Pakstis, A. J., Kidd, J. R., Lee, J.-F., Yin, S.-J., Ko, H.-C., Edenberg, H. J., Lu, R.-B., Kidd, K. K. Linkage disequilibrium at the ADH2 and ADH3 loci and risk of alcoholism. Am. J. Hum. Genet. 64: 1147-1157, 1999. [PubMed: 10090900] [Full Text: https://doi.org/10.1086/302317]
Roychoudhury, A. K., Nei, M. Human Polymorphic Genes: World Distribution. New York: Oxford Univ. Press (pub.) 1988.
Smith, M., Hopkinson, D. A., Harris, H. Alcohol dehydrogenase isozymes in adult human stomach and liver: evidence for activity of the ADH(3) locus. Ann. Hum. Genet. 35: 243-253, 1972. [PubMed: 5072686] [Full Text: https://doi.org/10.1111/j.1469-1809.1957.tb01398.x]
Smith, M., Hopkinson, D. A., Harris, H. Studies on the subunit structure and molecular size of the human dehydrogenase isozymes determined by the different loci, ADH(1), ADH(2), and ADH(3). Ann. Hum. Genet. 36: 401-414, 1973. [PubMed: 4748759] [Full Text: https://doi.org/10.1111/j.1469-1809.1973.tb00604.x]
Tolstrup, J. S., Nordestgaard, B. G., Rasmussen, S., Tybjaerg-Hansen, A., Gronbaek, M. Alcoholism and alcohol drinking habits predicted from alcohol dehydrogenase genes. Pharmacogenomics J. 8: 220-227, 2008. [PubMed: 17923853] [Full Text: https://doi.org/10.1038/sj.tpj.6500471]
Xu, Y., Carr, L. G., Bosron, W. F., Li, T.-K., Edenberg, H. J. Genotyping of human alcohol dehydrogenases at the ADH2 and ADH3 loci following DNA sequence amplification. Genomics 2: 209-214, 1988. [PubMed: 3397059] [Full Text: https://doi.org/10.1016/0888-7543(88)90004-3]
Zgombic-Knight, M., Deltour, L., Haselbeck, R. J., Foglio, M. H., Duester, G. Gene structure and promoter for Adh3 encoding mouse class IV alcohol dehydrogenase (retinol dehydrogenase). Genomics 41: 105-109, 1997. [PubMed: 9126489] [Full Text: https://doi.org/10.1006/geno.1997.4637]