The Investigation into CYP2E1 in Relation to the Level of Response to Alcohol Through a Combination of Linkage and Association Analysis

Amy Webb, Penelope A. Lind, Jelger Kalmijn, Heidi Feiler, Tom L. Smith, Marc A. Schuckit, Kirk C. Wilhelmsen

Research output: Contribution to journalArticle

26 Citations (Scopus)

Abstract

Background: A low level of response to alcohol during an individual's early experience with alcohol is associated with an increase risk of alcoholism. A family-based genome-wide linkage analysis using sibling pairs that underwent an alcohol challenge where the level of response to alcohol was measured with the Subjective High Assessment Scale (SHAS) implicated the 10q terminal (10qter) region. CYP2E1, a gene known for its involvement with ethanol metabolism, maps to this region.Methods: Variance component multipoint linkage analysis was performed on a combined map of single-nucleotide polymorphism (SNP) and microsatellite data. To account for the heterogeneity evident in the dataset, a calculation assuming locus heterogeneity was made using the Heterogeneity Log of Odds (HLOD) score. Association between SNP marker allele counts and copy number and SHAS scores were evaluated using a logistic regression model.Results: Linkage analysis detected significant linkage to CYP2E1, which was diminished because of apparent locus heterogeneity traced to a single family with extreme phenotypes. In retrospect, circumstances recorded during testing for this family suggest that their phenotype data are likely to be unreliable. Significant allelic associations were detected for several CYP2E1 polymorphisms and the SHAS score. DNA sequencing from families that contributed the greatest evidence for linkage did not detect any changes directly affecting the primary amino acid sequence. With the removal of a single family, combined evidence from microsatellites and SNPs offers significant linkage between the level of response to alcohol and the region on the end of chromosome 10.Conclusion: Combined linkage and association indicate that sequence changes in or near CYP2E1 affect the level of response to alcohol providing a predictor of risk of alcoholism. The absence of coding sequence changes indicates that regulatory sequences are responsible. Implicating CYP2E1 in the level of response to alcohol allows inferences to be made about how the brain perceives alcohol.

Original languageEnglish (US)
Pages (from-to)10-18
Number of pages9
JournalAlcoholism: Clinical and Experimental Research
Volume35
Issue number1
DOIs
StatePublished - Jan 2011
Externally publishedYes

Fingerprint

Cytochrome P-450 CYP2E1
Alcohols
Polymorphism
Single Nucleotide Polymorphism
Microsatellite Repeats
Alcoholism
Nucleotides
Genes
Logistic Models
Phenotype
Chromosomes, Human, Pair 10
Chromosomes
DNA Sequence Analysis
Metabolism
Logistics
Amino Acid Sequence
Brain
Ethanol
Alleles
Genome

Keywords

  • Association Analysis
  • Combined Linkage and Association
  • CYP2E1
  • Level of Response to Alcohol
  • Linkage Analysis
  • Locus Heterogeneity

ASJC Scopus subject areas

  • Medicine (miscellaneous)
  • Psychiatry and Mental health
  • Toxicology

Cite this

The Investigation into CYP2E1 in Relation to the Level of Response to Alcohol Through a Combination of Linkage and Association Analysis. / Webb, Amy; Lind, Penelope A.; Kalmijn, Jelger; Feiler, Heidi; Smith, Tom L.; Schuckit, Marc A.; Wilhelmsen, Kirk C.

In: Alcoholism: Clinical and Experimental Research, Vol. 35, No. 1, 01.2011, p. 10-18.

Research output: Contribution to journalArticle

Webb, Amy ; Lind, Penelope A. ; Kalmijn, Jelger ; Feiler, Heidi ; Smith, Tom L. ; Schuckit, Marc A. ; Wilhelmsen, Kirk C. / The Investigation into CYP2E1 in Relation to the Level of Response to Alcohol Through a Combination of Linkage and Association Analysis. In: Alcoholism: Clinical and Experimental Research. 2011 ; Vol. 35, No. 1. pp. 10-18.
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AU - Smith, Tom L.

AU - Schuckit, Marc A.

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