Genetic Epidemiology, Psychiatric Genetics, Asthma Genetics and Statistical Genetics Laboratories investigate the pattern of disease in families, particularly identical and non-identical twins, to assess the relative importance of genes and environment in a variety of important health problems.
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PMID
20958328
TITLE
The investigation into CYP2E1 in relation to the level of response to alcohol through a combination of linkage and association analysis.
ABSTRACT
BACKGROUND NlmCategory: 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 NlmCategory: 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 NlmCategory: 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 NlmCategory: 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.
Copyright 2010 by the Research Society on Alcoholism.
DATE PUBLISHED
2011 Jan
HISTORY
PUBSTATUS PUBSTATUSDATE
aheadofprint 2010/10/19
entrez 2010/10/21 06:00
pubmed 2010/10/21 06:00
medline 2011/06/24 06:00
AUTHORS
NAME COLLECTIVENAME LASTNAME FORENAME INITIALS AFFILIATION AFFILIATIONINFO
Webb A Webb Amy A Department of Biomedical Engineering, University of North Carolina at Chapel Hill, USA.
Lind PA Lind Penelope A PA
Kalmijn J Kalmijn Jelger J
Feiler HS Feiler Heidi S HS
Smith TL Smith Tom L TL
Schuckit MA Schuckit Marc A MA
Wilhelmsen K Wilhelmsen Kirk K
INVESTIGATORS
JOURNAL
VOLUME: 35
ISSUE: 1
TITLE: Alcoholism, clinical and experimental research
ISOABBREVIATION: Alcohol. Clin. Exp. Res.
YEAR: 2011
MONTH: Jan
DAY:
MEDLINEDATE:
SEASON:
CITEDMEDIUM: Internet
ISSN: 1530-0277
ISSNTYPE: Electronic
MEDLINE JOURNAL
MEDLINETA: Alcohol Clin Exp Res
COUNTRY: England
ISSNLINKING: 0145-6008
NLMUNIQUEID: 7707242
PUBLICATION TYPE
PUBLICATIONTYPE TEXT
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
COMMENTS AND CORRECTIONS
REFTYPE REFSOURCE REFPMID NOTE
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GRANTS
GRANTID AGENCY COUNTRY
AA05526 NIAAA NIH HHS United States
AA08403 NIAAA NIH HHS United States
M01 RR000083 NCRR NIH HHS United States
M01 RR000083-37S10426 NCRR NIH HHS United States
P20 RR020751 NCRR NIH HHS United States
P20 RR020751-03 NCRR NIH HHS United States
GENERAL NOTE
KEYWORDS
MESH HEADINGS
DESCRIPTORNAME QUALIFIERNAME
Adult
Alcohol Drinking metabolism
Alcoholism genetics
Chromosomes, Human, Pair 10 genetics
Cytochrome P-450 CYP2E1 metabolism
DNA Copy Number Variations metabolism
Family metabolism
Female metabolism
Genetic Linkage metabolism
Genome-Wide Association Study metabolism
Genotype metabolism
Humans metabolism
Male metabolism
Parents metabolism
Polymorphism, Single Nucleotide metabolism
Risk Factors metabolism
Siblings metabolism
Smoking metabolism
Surveys and Questionnaires metabolism
Young Adult metabolism
SUPPLEMENTARY MESH
GENE SYMBOLS
CHEMICALS
REGISTRYNUMBER NAMEOFSUBSTANCE
EC 1.14.13.- Cytochrome P-450 CYP2E1
OTHER ID's
OTHERID SOURCE
NIHMS230852 NLM
PMC3005010 NLM