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The genetics of alcohol metabolism: role of alcohol dehydrogenase and aldehyde dehydrogenase variants.

Edenberg HJ - Alcohol Res Health (2007)

Bottom Line: Researchers to date primarily have studied coding variants in the ADH1 B, ADH1C, and ALDH2 genes that are associated with altered kinetic properties of the resulting enzymes.For example, certain ADH1B and ADH1C alleles encode particularly active ADH enzymes, resulting in more rapid conversion of alcohol (i.e., ethanol) to acetaldehyde; these alleles have a protective effect on the risk of alcoholism.A variant of the ALDH2 gene encodes an essentially inactive ALDH enzyme, resulting in acetaldehyde accumulation and a protective effect.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana, USA.

ABSTRACT
The primary enzymes involved in alcohol metabolism are alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH). Both enzymes occur in several forms that are encoded by different genes; moreover, there are variants (i.e., alleles) of some of these genes that encode enzymes with different characteristics and which have different ethnic distributions. Which ADH or ALDH alleles a person carries influence his or her level of alcohol consumption and risk of alcoholism. Researchers to date primarily have studied coding variants in the ADH1 B, ADH1C, and ALDH2 genes that are associated with altered kinetic properties of the resulting enzymes. For example, certain ADH1B and ADH1C alleles encode particularly active ADH enzymes, resulting in more rapid conversion of alcohol (i.e., ethanol) to acetaldehyde; these alleles have a protective effect on the risk of alcoholism. A variant of the ALDH2 gene encodes an essentially inactive ALDH enzyme, resulting in acetaldehyde accumulation and a protective effect. It is becoming clear that noncoding variants in both ADH and ALDH genes also may influence alcohol metabolism and, consequently, alcoholism risk; the specific nature and effects of these variants still need further study.

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Related in: MedlinePlus

Linkage disequilibrium (LD) among single-nucleotide polymorphisms (SNPs) in the alcohol dehydrogenase (ADH) genes. The positions of the genes are indicated at the top. SNPs in which particular combinations of alleles are commonly inherited together have a high LD, depicted in the figure as darker-shaded boxes at the intersections of the SNPs that are being compared. SNPs in which combinations of alleles essentially are random have a lower LD (indicated by lighter shades). SNPs within genes generally are in high LD with each other, whereas SNPs in different genes typically have a lower LD between them. One region of moderately high LD spans most of the genes except ADH7. At one site of the ADH7 gene, frequent rearrangement of the genetic information (i.e., recombination) has occurred so that SNPs upstream of that site are randomly associated with SNPs downstream of that site (as indicated by the area of mostly white boxes).SOURCE: Modified from Edenberg et al. 2006.
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f2-arh-30-1-5-13: Linkage disequilibrium (LD) among single-nucleotide polymorphisms (SNPs) in the alcohol dehydrogenase (ADH) genes. The positions of the genes are indicated at the top. SNPs in which particular combinations of alleles are commonly inherited together have a high LD, depicted in the figure as darker-shaded boxes at the intersections of the SNPs that are being compared. SNPs in which combinations of alleles essentially are random have a lower LD (indicated by lighter shades). SNPs within genes generally are in high LD with each other, whereas SNPs in different genes typically have a lower LD between them. One region of moderately high LD spans most of the genes except ADH7. At one site of the ADH7 gene, frequent rearrangement of the genetic information (i.e., recombination) has occurred so that SNPs upstream of that site are randomly associated with SNPs downstream of that site (as indicated by the area of mostly white boxes).SOURCE: Modified from Edenberg et al. 2006.

Mentions: SNPs occur as a result of mutations during the course of evolution, so each is initially associated with a particular pattern of other SNPs on the chromosome in which it arose. Over many generations, recombination reshuffles the pattern of SNPs, with closer SNPs less likely to be separated. Therefore, SNPs are not randomly sorted along chromosomes; the nonrandom coin-heritance of alleles, which is called LD, tends to be higher among nearby SNPs. There is strong LD between variants in the ADH1B and ADH1C genes, which complicates analyses of the effects of individual coding variations in those genes (Chen et al. 1999a; Osier et al. 1999, 2002b, 2004). The most extensive analysis to date of variations in the ADH gene region showed strong LD across nearly the entire region (Figure 2) (Edenberg et al. 2006). The LD was particularly striking in the regions encompassing the ADH1C–ADH1B and ADH4–ADH5 genes. Conversely, a site of frequent recombination occurs within the ADH7 gene, which means that variations near the start (i.e., in the 5′ portion) of that gene are nearly randomly associated with variations in the other ADH genes (Han et al. 2005; Edenberg et al. 2006). The strong LD over most of the ADH gene region means that the coding variations of those genes that have been most frequently studied are probably closely associated with regulatory variations, making it difficult to determine the exact contributions of individual variants—a fact that has not yet been widely appreciated.


The genetics of alcohol metabolism: role of alcohol dehydrogenase and aldehyde dehydrogenase variants.

Edenberg HJ - Alcohol Res Health (2007)

Linkage disequilibrium (LD) among single-nucleotide polymorphisms (SNPs) in the alcohol dehydrogenase (ADH) genes. The positions of the genes are indicated at the top. SNPs in which particular combinations of alleles are commonly inherited together have a high LD, depicted in the figure as darker-shaded boxes at the intersections of the SNPs that are being compared. SNPs in which combinations of alleles essentially are random have a lower LD (indicated by lighter shades). SNPs within genes generally are in high LD with each other, whereas SNPs in different genes typically have a lower LD between them. One region of moderately high LD spans most of the genes except ADH7. At one site of the ADH7 gene, frequent rearrangement of the genetic information (i.e., recombination) has occurred so that SNPs upstream of that site are randomly associated with SNPs downstream of that site (as indicated by the area of mostly white boxes).SOURCE: Modified from Edenberg et al. 2006.
© Copyright Policy - public-domain
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3860432&req=5

f2-arh-30-1-5-13: Linkage disequilibrium (LD) among single-nucleotide polymorphisms (SNPs) in the alcohol dehydrogenase (ADH) genes. The positions of the genes are indicated at the top. SNPs in which particular combinations of alleles are commonly inherited together have a high LD, depicted in the figure as darker-shaded boxes at the intersections of the SNPs that are being compared. SNPs in which combinations of alleles essentially are random have a lower LD (indicated by lighter shades). SNPs within genes generally are in high LD with each other, whereas SNPs in different genes typically have a lower LD between them. One region of moderately high LD spans most of the genes except ADH7. At one site of the ADH7 gene, frequent rearrangement of the genetic information (i.e., recombination) has occurred so that SNPs upstream of that site are randomly associated with SNPs downstream of that site (as indicated by the area of mostly white boxes).SOURCE: Modified from Edenberg et al. 2006.
Mentions: SNPs occur as a result of mutations during the course of evolution, so each is initially associated with a particular pattern of other SNPs on the chromosome in which it arose. Over many generations, recombination reshuffles the pattern of SNPs, with closer SNPs less likely to be separated. Therefore, SNPs are not randomly sorted along chromosomes; the nonrandom coin-heritance of alleles, which is called LD, tends to be higher among nearby SNPs. There is strong LD between variants in the ADH1B and ADH1C genes, which complicates analyses of the effects of individual coding variations in those genes (Chen et al. 1999a; Osier et al. 1999, 2002b, 2004). The most extensive analysis to date of variations in the ADH gene region showed strong LD across nearly the entire region (Figure 2) (Edenberg et al. 2006). The LD was particularly striking in the regions encompassing the ADH1C–ADH1B and ADH4–ADH5 genes. Conversely, a site of frequent recombination occurs within the ADH7 gene, which means that variations near the start (i.e., in the 5′ portion) of that gene are nearly randomly associated with variations in the other ADH genes (Han et al. 2005; Edenberg et al. 2006). The strong LD over most of the ADH gene region means that the coding variations of those genes that have been most frequently studied are probably closely associated with regulatory variations, making it difficult to determine the exact contributions of individual variants—a fact that has not yet been widely appreciated.

Bottom Line: Researchers to date primarily have studied coding variants in the ADH1 B, ADH1C, and ALDH2 genes that are associated with altered kinetic properties of the resulting enzymes.For example, certain ADH1B and ADH1C alleles encode particularly active ADH enzymes, resulting in more rapid conversion of alcohol (i.e., ethanol) to acetaldehyde; these alleles have a protective effect on the risk of alcoholism.A variant of the ALDH2 gene encodes an essentially inactive ALDH enzyme, resulting in acetaldehyde accumulation and a protective effect.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana, USA.

ABSTRACT
The primary enzymes involved in alcohol metabolism are alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH). Both enzymes occur in several forms that are encoded by different genes; moreover, there are variants (i.e., alleles) of some of these genes that encode enzymes with different characteristics and which have different ethnic distributions. Which ADH or ALDH alleles a person carries influence his or her level of alcohol consumption and risk of alcoholism. Researchers to date primarily have studied coding variants in the ADH1 B, ADH1C, and ALDH2 genes that are associated with altered kinetic properties of the resulting enzymes. For example, certain ADH1B and ADH1C alleles encode particularly active ADH enzymes, resulting in more rapid conversion of alcohol (i.e., ethanol) to acetaldehyde; these alleles have a protective effect on the risk of alcoholism. A variant of the ALDH2 gene encodes an essentially inactive ALDH enzyme, resulting in acetaldehyde accumulation and a protective effect. It is becoming clear that noncoding variants in both ADH and ALDH genes also may influence alcohol metabolism and, consequently, alcoholism risk; the specific nature and effects of these variants still need further study.

Show MeSH
Related in: MedlinePlus