Variants in Region of Ethanol Metabolism Gene Predict Alcoholism Risk

A search for genetic factors that influence individuals' early experience with ethanol has found variants in or near CYP2E1 associated with stronger responses and inebriation after relatively low alcohol intake.

The relationship between early reactions to alcohol and potential alcoholism was already recognized, with lower responses to ethanol associated with greater alcoholism risk.

However, the new study reports a genetic association with response levels, which may serve as a predictor — and possible treatment target — for alcoholism.

The new study, which combines behavioral assessments of response to an alcohol challenge with genetic mapping of single nucleotide polymorphisms (SNPs) and microsatellites, was published online October 19 in Alcoholism: Clinical and Experimental Research.

"It turns out that a specific version or allele of CYP2E1 makes people more sensitive to alcohol," senior author Kirk Wilhelmsen, MD, PhD, professor, Department of Genetics, University of North Carolina School of Medicine, Chapel Hill, said in a university press release.

"The conventional model basically says that alcohol affects how neurotransmitters...do their job. But our findings suggest it is even more complex than that," Dr. Wilhelmsen noted.

Participants in stage 1 of the study were 139 sibling pairs of college students 18 to 29 years old, who were not alcohol-dependent but who had at least 1 parent with alcohol dependency. DNA for genomic analyses was obtained from peripheral blood samples.

Participants underwent a 3-hour alcohol challenge that began with consuming a 20%:80% mixture of 95% ethanol and soda in 8 minutes. Total ethanol intake was .75 mL/kg for women and .9 mL/kg for men. Scores on the Subjective High Assessment Scale (SHAS), body sway, and breath alcohol levels were obtained before the challenge and regularly throughout.

The SHAS questionnaire measures participants' level of response to alcohol with questions about their feelings: drunk, sleepy, and similar self-perceptions. The genomewide genetic analysis looked for genetic variants associated with the changes in SHAS and body sway scores from baseline to 1 hour.

Using "variance component analysis," investigators found that the SHAS scores had a significant association with a region on the long arm of chromosome 10. Within this region, CYP2E1 was already recognized as having a role in ethanol metabolism.

"The CYP2E1 enzyme metabolizes ethanol and acetaminophen, as well as many toxicologic and carcinogenic compounds and can be induced by ethanol and nicotine," the authors write. In fact, CYP2E1 is part of the system that oxidizes ethanol in the liver, producing toxic breakdown products and oxidative stress that may cause liver damage.

Adding 99 more sibling pairs in the second stage of the study decreased the strength of the association strikingly; however, this result was soon traced to a single family. An indication of its outlier effect is that most families had family-specific heterogeneity scores of .99, but the outlier family's score was .37 — one sibling of this pair had a SHAS score of 26.75, whereas their sibling's SHAS score was 4, despite inheriting the same chromosome from both their parents. Removing this single family from the analysis restored the strong association between SHAS scores and CYP2E1.

The investigators examined 10 SNPs in or near CYP2E1, finding the strongest association for SNP rs10776687. Regression analysis for genotype and SHAS score obtained P = .007 for this SNP; rs10776687 also explained 4.6% of the SHAS score variance.

The authors acknowledge, however, that the response to alcohol might be influenced by a nearby SNP not yet identified or by combined effects of several polymorphisms in the CYP2E1 region. "It still can be concluded [that] regulatory sequences near CYP2E1 appear to play a role in the level of response to alcohol," the report observes.

CYP2E1 is implicated not only in response to ethanol but also in metabolizing carcinogenic compounds and in several types of cancer. Reactive oxygen species produced by CYP2E1 oxidation may react with DNA and lead to mutant cells that resist apoptosis.

"It appears that alleles that increase CYP2E1 expression increase the level of response to alcohol and risk of cancer," they conclude. Noting that several lines of evidence connect CYP2E1 with alcohol use and outcomes, they suggest that the gene provides a risk predictor for alcoholism. In addition: "Drugs that affect the expression of this gene and, subsequently, the perception of alcohol, could reduce intoxication or limit consumption and thus moderate the development of alcoholism."

The study was supported by the University of California–San Francisco, the Veterans Affairs Research Service, and the National Institute on Alcohol Abuse and Alcoholism.

Alcohol Clin Exp Res. Published online October 19, 2010.

source: medscape