The investigation into CYP2E1 in relation to the level of response to alcohol through a combination of linkage and association analysis.
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.


CONCLUSIONS
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.
Webb
Amy
A
Department of Biomedical Engineering, University of North Carolina at Chapel Hill, USA.
Lind
Penelope A
PA
Kalmijn
Jelger
J
Feiler
Heidi S
HS
Smith
Tom L
TL
Schuckit
Marc A
MA
Wilhelmsen
Kirk
K
D000328:Adult; D000428:Alcohol Drinking / Q000235:genetics / Q000378:metabolism*; D000437:Alcoholism / Q000235:genetics*; D002879:Chromosomes, Human, Pair 10; D019392:Cytochrome P-450 CYP2E1 / Q000235:genetics* / Q000378:metabolism; D056915:DNA Copy Number Variations; D005190:Family; D005260:Female; D008040:Genetic Linkage; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D008297:Male; D010290:Parents; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors; D035781:Siblings; D012907:Smoking; D011795:Surveys and Questionnaires; D055815:Young Adult
D019392:Cytochrome P-450 CYP2E1