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

paper Cited Public

Authors: Webb, Amy; Lind, Penelope A; Kalmijn, Jelger; Feiler, Heidi S; Smith, Tom L; Schuckit, Marc A; Wilhelmsen, Kirk
Year: 2011
Journal: Alcoholism, clinical and experimental research
PMID: 20958328
DOI: 10.1111/j.1530-0277.2010.01317.x
PMCID: PMC3005010

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.

#	Section	Preview
0	Introduction	While a number of phenotypic factors can affect the risk for alcoholism, one of the most studied…
1	Introduction	at historically higher risk for alcoholism, such as Native American or Korean, need to consume…
2	Introduction	Initially, data were collected from 139 sibling pairs (Wilhelmsen et al., 2003). Variance component…
3	Introduction	Most of the ethanol that is consumed is oxidized by the liver using alcohol dehydrogenase (ADH). At…
4	Introduction	CYP2E1 is part of the Microsomal Ethanol Oxidizing System (MEOS) accounting for up to 10% of ethanol…
5	Introduction	intake of electrons leading to an increase of superoxide anions (Seitz and Stickel, 2007). The…
6	Introduction	The catalase pathway can oxidize ethanol in conjunction with hydrogen peroxide generating systems,…
7	Introduction	High ethanol concentrations can interfere with the ability of CYP2E1 to metabolize other substrates…
8	Introduction	A number of polymorphisms in CYP2E1 have been tested in relation to alcoholism and a number of…
9	Introduction	Due to the previously described relationship between CYP2E1 and the metabolism of ethanol and…
10	Methods — Alcohol Challenge	The data collection protocol was approved by the Human Subjects Protection Committee at the…
11	Methods — Alcohol Challenge	To measure each participant’s response to alcohol, the Subjective High Assessment Scale (SHAS)…
12	Methods — Taqman Genotyping	Genomic DNA was extracted from whole peripheral blood samples. Genotyping was performed on 10 SNPs…
13	Methods — Copy number analysis	The copy number of CYP2E1 was determined for each sample in quadruplicate through the amplification…
14	Methods — CYP2E1 resequencing	Index cases from the 96 families with the greatest evidence for linkage to the 10q terminal region…
15	Methods — Linkage allowing for heterogeneity	A map of the positions of the genotyped SNPs relative to the microsatellite markers was created with…
16	Methods — Association analysis	Association between SNP marker allele counts and copy number and SHAS scores were evaluated using a…
17	Methods — Combined Linkage and Association	Combined linkage and association analysis using SOLAR v4.0.7 was performed to include identity by…
18	Methods — Combined Linkage and Association	By combining linkage and association approaches, a disease loci position can be confined to a region…
19	Results	With a combined map of microsatellite and SNP markers the dataset was reanalyzed, as described in…

Name	Type
10qter local	variant
1 copy local	phenotype
2 copies local	phenotype
>3 copies local	phenotype
3 copies local	phenotype
4-hydroxynonenal	drug
5-HT	drug
96 families local	cohort
acetaldehyde	drug
acetaminophen	drug
acetic acid	drug
ADH	gene
African American	cohort
alcohol	phenotype
alcohol dependence	phenotype
alcoholic liver disease	phenotype
alcoholism	phenotype
alcohol related liver disease local	phenotype
alcohol sensitivity	phenotype
alcohol use disorders	phenotype
amount consumed 24 hours prior to challenge local	phenotype
antibody response local	phenotype
Asian	cohort
ATP	drug
average number of drinks consumed on days the subject consumed alcohol local	phenotype
blood alcohol level	phenotype
Body sway	phenotype
brain	anatomy
Breath alcohol level	phenotype
cancer	phenotype
CAT	gene
Catalase knockout mice local	cohort
Caucasian population	cohort
Caucasians	cohort
children of alcoholics	cohort
chronic alcoholism	phenotype
cigarettes	phenotype
college students	cohort
Combined sibling pairs local	cohort
copy number local	variant
Copy number of CYP2E1 local	variant
CYP2E1	gene
CYP2E1*1B local	variant
CYP2E1*1D local	variant
CYP2E1*5B local	variant
CYP2E1*5B c1 local	variant
CYP2E1*5B c1 allele local	variant
CYP2E1*5B c2 local	variant
CYP2E1*5B c2 allele local	variant
CYP2E1*6 local	variant
CYP2E1 c2 allele local	variant
CYP2E1 copy number local	variant
CYP2E1 knockout mice local	cohort
CYP2E1 variant local	variant
decreased DNA repair local	phenotype
digestive system cancer local	phenotype
Discordant family local	cohort
elevated CYP2E1 activity local	phenotype
Elevated CYP2E1 activity local	phenotype
ethanol consumption	phenotype
ethanol users with chronic liver disease local	cohort
excessive alcohol consumption	phenotype
Fainting local	phenotype
families	cohort
Families with Strongest Evidence of Linkage local	cohort
family 44 local	cohort
GABA	phenotype
genetic variants	cohort
glutathione	drug
glutathione depletion local	phenotype
HapMap	cohort
heavy drinking	phenotype
hepatocellular carcinoma	phenotype
high blood acetaldehyde levels local	phenotype
Higher future drinking levels local	phenotype
human subjects	cohort
hydrogen peroxide	drug
Index cases local	cohort
Index Cases local	cohort
Japanese men local	cohort
Kcnma1	gene
Koreans	cohort
Linkage signal local	phenotype
liver injury	phenotype
LOD score local	phenotype
maximum amount drank in one day local	phenotype
Mexican American	cohort
Mexican Indians population local	cohort
NAD+	drug
NADH	drug
NADP+ local	drug
NADPH	drug
NADPH oxidase	drug
Native Americans	cohort
nicotine	drug
nicotine use	phenotype
non-smokers	phenotype
number of cigarettes smoked on days where the subject smoked local	phenotype
number of days of smoking in a month local	phenotype
number of days the subject drank in the last week local	phenotype
oral cavity cancer	phenotype
oxidative stress	phenotype
oxygen	drug
participants	cohort
Phenotyping error local	phenotype
procarcinogens local	drug
rats	cohort
reactive oxygen species	drug
Recent alcohol consumption	phenotype
respiratory system cancer local	phenotype
ROS	drug
rs10776687 local	variant
rs2031920 local	variant
rs2070676 local	variant
rs2515641 local	variant
Schuckit 2005 sibling pairs local	cohort
Self-Rating of the Effects of alcohol	phenotype
Sensitivity to sedative effects of ethanol local	phenotype
SHAS phenotype local	phenotype
SHAS score local	phenotype
sibling pairs	cohort
smoking	phenotype
smoking behavior	phenotype
SNP	cohort
Stage 1 samples local	cohort
Stage 2 samples local	cohort
Subjective High Assessment Scale	phenotype
Subjective High Assessment Scale (SHAS)	phenotype
subjects	cohort
superoxide anion	drug
Taiwanese population local	cohort
tobacco use	phenotype
wild-type mice	cohort
Wilhelmsen 2003 sibling pairs local	cohort

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