A novel polymorphism (-357 G/A) of the ALDH2 gene: Linkage disequilibrium and an association with alcoholism

Shoji Harada, Takehito Okubo, Takako Nakamura, Chieko Fujii, Fumio Nomura, Susumu Higuchi, Mikihiro Tsutsumi

Research output: Contribution to journalArticle

63 Citations (Scopus)

Abstract

Background: Human mitochondrial aldehyde dehydrogenase (ALDH2) is a major enzyme responsible for the oxidation of acetaldehyde derived from ethanol metabolism. The human ALDH2 gene shows genetic polymorphism at position 1510 with a G to A transition in exon 12. This mutation leads to ALDH2 enzyme deficiency and protection against alcoholism. As yet, no polymorphism for the promoter region of the ALDH2 gene has been reported. Methods: We analyzed 600 nucleotides of the promoter region in addition to exon 12 from 571 Japanese, 68 Chinese, 80 Myanmar, 60 Mongolians, and 82 North-American Caucasians using single-strand conformational change polymorphism (SSCP) analysis and the polymerase chain reaction (PCR). PCR products that showed an aberrant banding pattern detected by the SSCP analysis were subjected to PCR direct sequencing. Results: A novel polymorphism at -357 with a G to A substitution was found in all the population groups, including North-American Caucasians. In addition, the polymorphic status in the promoter and exon 12 suggested linkage disequilibrium between the two loci, which indicated that among Japanese, the ALDH2*2 allele is linked to the G promoter allele, and the ALDH2*1 allele is linked to the A allele. A total of 206 healthy male controls and 185 alcoholic male patients with the homozygous ALDH2*1 genotype were analyzed for the polymorphism in the promoter. Genotypic frequencies of GG, GA, and AA for alcoholics were 54.1%, 44.3%, and 1.6%, and those for controls were 52.9%, 40.3%, and 6.8%, respectively. The A allele frequencies for alcoholics and controls were 0.24 and 0.27, respectively. A χ2 test for the entire 3 x 2 table indicated significant variations in the three genotypes (χ2 = 6.40, p < 0.05). However, no significant difference in allelic frequencies between the two groups was observed. Conclusion: This new polymorphism in the ALDH2 promoter is present in all populations studied. Further analysis in other ethnic groups is necessary to establish this as an additional risk factor for alcoholism.

Original languageEnglish
Pages (from-to)958-962
Number of pages5
JournalAlcoholism: Clinical and Experimental Research
Volume23
Issue number6
Publication statusPublished - 1999 Jun
Externally publishedYes

Fingerprint

Linkage Disequilibrium
Polymorphism
Alcoholism
Genes
Alleles
Association reactions
Exons
Alcoholics
Genetic Promoter Regions
Polymerase chain reaction
Polymerase Chain Reaction
Genotype
Myanmar
Acetaldehyde
Genetic Polymorphisms
Enzymes
Population Groups
Ethnic Groups
Gene Frequency
Ethanol

Keywords

  • Alcoholism
  • Linkage Disequilibrium
  • Mitochondrial Aldehyde Dehydrogenase
  • New Allele
  • Promoter

ASJC Scopus subject areas

  • Medicine (miscellaneous)
  • Toxicology

Cite this

A novel polymorphism (-357 G/A) of the ALDH2 gene : Linkage disequilibrium and an association with alcoholism. / Harada, Shoji; Okubo, Takehito; Nakamura, Takako; Fujii, Chieko; Nomura, Fumio; Higuchi, Susumu; Tsutsumi, Mikihiro.

In: Alcoholism: Clinical and Experimental Research, Vol. 23, No. 6, 06.1999, p. 958-962.

Research output: Contribution to journalArticle

Harada, S, Okubo, T, Nakamura, T, Fujii, C, Nomura, F, Higuchi, S & Tsutsumi, M 1999, 'A novel polymorphism (-357 G/A) of the ALDH2 gene: Linkage disequilibrium and an association with alcoholism', Alcoholism: Clinical and Experimental Research, vol. 23, no. 6, pp. 958-962.
Harada, Shoji ; Okubo, Takehito ; Nakamura, Takako ; Fujii, Chieko ; Nomura, Fumio ; Higuchi, Susumu ; Tsutsumi, Mikihiro. / A novel polymorphism (-357 G/A) of the ALDH2 gene : Linkage disequilibrium and an association with alcoholism. In: Alcoholism: Clinical and Experimental Research. 1999 ; Vol. 23, No. 6. pp. 958-962.
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abstract = "Background: Human mitochondrial aldehyde dehydrogenase (ALDH2) is a major enzyme responsible for the oxidation of acetaldehyde derived from ethanol metabolism. The human ALDH2 gene shows genetic polymorphism at position 1510 with a G to A transition in exon 12. This mutation leads to ALDH2 enzyme deficiency and protection against alcoholism. As yet, no polymorphism for the promoter region of the ALDH2 gene has been reported. Methods: We analyzed 600 nucleotides of the promoter region in addition to exon 12 from 571 Japanese, 68 Chinese, 80 Myanmar, 60 Mongolians, and 82 North-American Caucasians using single-strand conformational change polymorphism (SSCP) analysis and the polymerase chain reaction (PCR). PCR products that showed an aberrant banding pattern detected by the SSCP analysis were subjected to PCR direct sequencing. Results: A novel polymorphism at -357 with a G to A substitution was found in all the population groups, including North-American Caucasians. In addition, the polymorphic status in the promoter and exon 12 suggested linkage disequilibrium between the two loci, which indicated that among Japanese, the ALDH2*2 allele is linked to the G promoter allele, and the ALDH2*1 allele is linked to the A allele. A total of 206 healthy male controls and 185 alcoholic male patients with the homozygous ALDH2*1 genotype were analyzed for the polymorphism in the promoter. Genotypic frequencies of GG, GA, and AA for alcoholics were 54.1{\%}, 44.3{\%}, and 1.6{\%}, and those for controls were 52.9{\%}, 40.3{\%}, and 6.8{\%}, respectively. The A allele frequencies for alcoholics and controls were 0.24 and 0.27, respectively. A χ2 test for the entire 3 x 2 table indicated significant variations in the three genotypes (χ2 = 6.40, p < 0.05). However, no significant difference in allelic frequencies between the two groups was observed. Conclusion: This new polymorphism in the ALDH2 promoter is present in all populations studied. Further analysis in other ethnic groups is necessary to establish this as an additional risk factor for alcoholism.",
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T1 - A novel polymorphism (-357 G/A) of the ALDH2 gene

T2 - Linkage disequilibrium and an association with alcoholism

AU - Harada, Shoji

AU - Okubo, Takehito

AU - Nakamura, Takako

AU - Fujii, Chieko

AU - Nomura, Fumio

AU - Higuchi, Susumu

AU - Tsutsumi, Mikihiro

PY - 1999/6

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N2 - Background: Human mitochondrial aldehyde dehydrogenase (ALDH2) is a major enzyme responsible for the oxidation of acetaldehyde derived from ethanol metabolism. The human ALDH2 gene shows genetic polymorphism at position 1510 with a G to A transition in exon 12. This mutation leads to ALDH2 enzyme deficiency and protection against alcoholism. As yet, no polymorphism for the promoter region of the ALDH2 gene has been reported. Methods: We analyzed 600 nucleotides of the promoter region in addition to exon 12 from 571 Japanese, 68 Chinese, 80 Myanmar, 60 Mongolians, and 82 North-American Caucasians using single-strand conformational change polymorphism (SSCP) analysis and the polymerase chain reaction (PCR). PCR products that showed an aberrant banding pattern detected by the SSCP analysis were subjected to PCR direct sequencing. Results: A novel polymorphism at -357 with a G to A substitution was found in all the population groups, including North-American Caucasians. In addition, the polymorphic status in the promoter and exon 12 suggested linkage disequilibrium between the two loci, which indicated that among Japanese, the ALDH2*2 allele is linked to the G promoter allele, and the ALDH2*1 allele is linked to the A allele. A total of 206 healthy male controls and 185 alcoholic male patients with the homozygous ALDH2*1 genotype were analyzed for the polymorphism in the promoter. Genotypic frequencies of GG, GA, and AA for alcoholics were 54.1%, 44.3%, and 1.6%, and those for controls were 52.9%, 40.3%, and 6.8%, respectively. The A allele frequencies for alcoholics and controls were 0.24 and 0.27, respectively. A χ2 test for the entire 3 x 2 table indicated significant variations in the three genotypes (χ2 = 6.40, p < 0.05). However, no significant difference in allelic frequencies between the two groups was observed. Conclusion: This new polymorphism in the ALDH2 promoter is present in all populations studied. Further analysis in other ethnic groups is necessary to establish this as an additional risk factor for alcoholism.

AB - Background: Human mitochondrial aldehyde dehydrogenase (ALDH2) is a major enzyme responsible for the oxidation of acetaldehyde derived from ethanol metabolism. The human ALDH2 gene shows genetic polymorphism at position 1510 with a G to A transition in exon 12. This mutation leads to ALDH2 enzyme deficiency and protection against alcoholism. As yet, no polymorphism for the promoter region of the ALDH2 gene has been reported. Methods: We analyzed 600 nucleotides of the promoter region in addition to exon 12 from 571 Japanese, 68 Chinese, 80 Myanmar, 60 Mongolians, and 82 North-American Caucasians using single-strand conformational change polymorphism (SSCP) analysis and the polymerase chain reaction (PCR). PCR products that showed an aberrant banding pattern detected by the SSCP analysis were subjected to PCR direct sequencing. Results: A novel polymorphism at -357 with a G to A substitution was found in all the population groups, including North-American Caucasians. In addition, the polymorphic status in the promoter and exon 12 suggested linkage disequilibrium between the two loci, which indicated that among Japanese, the ALDH2*2 allele is linked to the G promoter allele, and the ALDH2*1 allele is linked to the A allele. A total of 206 healthy male controls and 185 alcoholic male patients with the homozygous ALDH2*1 genotype were analyzed for the polymorphism in the promoter. Genotypic frequencies of GG, GA, and AA for alcoholics were 54.1%, 44.3%, and 1.6%, and those for controls were 52.9%, 40.3%, and 6.8%, respectively. The A allele frequencies for alcoholics and controls were 0.24 and 0.27, respectively. A χ2 test for the entire 3 x 2 table indicated significant variations in the three genotypes (χ2 = 6.40, p < 0.05). However, no significant difference in allelic frequencies between the two groups was observed. Conclusion: This new polymorphism in the ALDH2 promoter is present in all populations studied. Further analysis in other ethnic groups is necessary to establish this as an additional risk factor for alcoholism.

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KW - Mitochondrial Aldehyde Dehydrogenase

KW - New Allele

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