Mapping of quantitative trait loci underlying ethanol metabolism in BXD recombinant inbred mouse strains

Judith E. Grisel, Pamela Metten, Charlotte D. Wenger, Catherine M. Merrill, John Jr Crabbe

Research output: Contribution to journalArticle

36 Citations (Scopus)

Abstract

Background: Genetic factors are well known to play an important role in determining individual differences in the metabolism of ethanol (EtOH), and several specific polymorphic loci have been identified that significantly contribute to the variability of EtOH metabolism in humans. However, these variant genes are either alcohol or aldehyde dehydrogenases, and the identification of new gene products that contribute to variation in alcohol metabolism would be useful. Methods: To identify quantitative trait loci (QTLs), we correlated variation in polymorphic markers with blood EtOH concentration and the rate of EtOH metabolism (β) in C57BL/6J and DBA/2J strains and in 25 of their recombinant inbred strains after 2 and 3 g/kg of EtOH intraperitoneally. Results: A QTL associated with β values for both doses was definitively mapped to the proximal region of chromosome 17, syntenic with human chromosome 6q25-27. Seven to 12 chromosomal regions were provisionally identified for each phenotype; several were associated with 2 or more phenotypes. Each QTL suggests the location of a gene or genes affecting EtOH pharmacokinetics. Candidate genes suggested by these analyses included several whose gene products are known to be induced by EtOH (e.g., superoxide dismutase, glutathione transferase, and cytochrome P450 2E1), as well as several whose gene products have signaling functions likely to contribute to this induction. Conclusions: These studies provide evidence for the existence of genes affecting EtOH metabolism in multiple chromosomal regions. Future studies will be required to identify the chromosome 17 gene product. Use of other genetic populations, such as B6D2F2 crosses, will be required to determine which of the provisional loci represent true and which represent false-positive associations.

Original languageEnglish (US)
Pages (from-to)610-616
Number of pages7
JournalAlcoholism: Clinical and Experimental Research
Volume26
Issue number5
StatePublished - 2002

Fingerprint

Inbred Strains Mice
Quantitative Trait Loci
Metabolism
Ethanol
Genes
Chromosomes
Chromosomes, Human, Pair 17
Phenotype
Cytochrome P-450 CYP2E1
Aldehyde Dehydrogenase
Alcohol Dehydrogenase
Population Genetics
Genetic Association Studies
Human Chromosomes
Pharmacokinetics
Glutathione Transferase
Individuality
Superoxide Dismutase
Alcohols
Blood

Keywords

  • Alcohol Pharmacokinetics
  • BXD Recombinant Inbred Strains
  • Gene Mapping
  • Pharmacogenetics
  • QTL

ASJC Scopus subject areas

  • Medicine (miscellaneous)
  • Toxicology

Cite this

Mapping of quantitative trait loci underlying ethanol metabolism in BXD recombinant inbred mouse strains. / Grisel, Judith E.; Metten, Pamela; Wenger, Charlotte D.; Merrill, Catherine M.; Crabbe, John Jr.

In: Alcoholism: Clinical and Experimental Research, Vol. 26, No. 5, 2002, p. 610-616.

Research output: Contribution to journalArticle

Grisel, Judith E. ; Metten, Pamela ; Wenger, Charlotte D. ; Merrill, Catherine M. ; Crabbe, John Jr. / Mapping of quantitative trait loci underlying ethanol metabolism in BXD recombinant inbred mouse strains. In: Alcoholism: Clinical and Experimental Research. 2002 ; Vol. 26, No. 5. pp. 610-616.
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N2 - Background: Genetic factors are well known to play an important role in determining individual differences in the metabolism of ethanol (EtOH), and several specific polymorphic loci have been identified that significantly contribute to the variability of EtOH metabolism in humans. However, these variant genes are either alcohol or aldehyde dehydrogenases, and the identification of new gene products that contribute to variation in alcohol metabolism would be useful. Methods: To identify quantitative trait loci (QTLs), we correlated variation in polymorphic markers with blood EtOH concentration and the rate of EtOH metabolism (β) in C57BL/6J and DBA/2J strains and in 25 of their recombinant inbred strains after 2 and 3 g/kg of EtOH intraperitoneally. Results: A QTL associated with β values for both doses was definitively mapped to the proximal region of chromosome 17, syntenic with human chromosome 6q25-27. Seven to 12 chromosomal regions were provisionally identified for each phenotype; several were associated with 2 or more phenotypes. Each QTL suggests the location of a gene or genes affecting EtOH pharmacokinetics. Candidate genes suggested by these analyses included several whose gene products are known to be induced by EtOH (e.g., superoxide dismutase, glutathione transferase, and cytochrome P450 2E1), as well as several whose gene products have signaling functions likely to contribute to this induction. Conclusions: These studies provide evidence for the existence of genes affecting EtOH metabolism in multiple chromosomal regions. Future studies will be required to identify the chromosome 17 gene product. Use of other genetic populations, such as B6D2F2 crosses, will be required to determine which of the provisional loci represent true and which represent false-positive associations.

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