Variants in Region of Ethanol Metabolism Gene Predict Alcoholism Risk

Jacquelyn K. Beals, PhD

October 22, 2010

October 22, 2010 ( Updated With Comment ) — 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 general idea for how alcohol affects the brain has undergone evolution over time," senior study author Kirk Wilhelmsen, MD, PhD, professor, Department of Genetics, University of North Carolina School of Medicine, Chapel Hill, told Medscape Medical News.

"Historically the idea was that since alcohol is lipid soluble like other anesthetics, it was effective through the membranes of cells. That idea has gradually been dispensed with, not really with a lot of data, but it’s gradually been replaced by the neurotransmitter model.

"Our identifying this gene with how you perceive alcohol actually returns to a metabolic model, and that’s probably pretty important," Dr. Wilhelmsen added.

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," Dr. Wilhelmsen said in a university press release.

"The conventional model basically says that alcohol affects how their job. But our findings suggest it is even more complex than that."

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.

"If you take a 160- to 170-pound man (about 75-80 kg), you’re talking about nearly 70 grams of alcohol — this is a fairly substantial amount of alcohol," commented Howard J. Edenberg, PhD, professor of biochemistry and molecular biology and of medical and molecular genetics and director of the Center for Medical Genomics, Indiana University School of Medicine, Indianapolis.

"Women are typically dosed less, not so much for the activity of their ADH [alcohol dehydrogenase], but because alcohol typically distributes in body water and, per kilogram, women have a little less body water than men," Dr. Edenberg told Medscape Medical News.

Participants' scores on the Subjective High Assessment Scale (SHAS), body sway, and breath alcohol levels were obtained before the challenge and regularly throughout.

"If you look at this [SHAS] questionnaire, it has Likert scales on it," said Dr. Wilhelmsen. "Do you feel nauseous or do you feel normal, extremely nauseous or normal? Do you feel extremely dizzy vs normal? And it goes through a list of 20 of these. Basically, it doesn’t matter very much what the specific descriptor is, but how much the person reports being affected: 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 study 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 reduced the strength of the association strikingly; however, this result was soon traced to a single family. 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, and rs10776687 explained 4.6% of the SHAS score variance.

The study 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.

"Since several lines of evidence connect CYP2E1 with alcohol use and outcomes,the may gene provide a risk predictor for alcoholism. In addition, the study authors suggest, "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.

"One of the clear messages that has to come across every time you have an article about genetics of alcoholism is that it’s a complex disease," observed Dr. Edenberg. "We’re not talking about genes that will make you be an alcoholic or protect you from being an alcoholic. We’re talking about genes that interact with the environment, that tip a balance one way or another," said Dr. Edenberg.

"I’m encouraged by the work in general in the area, but I don’t think any one piece of it should be oversold," he added.

Dr. Wilhelmsen and Dr. Edenberg have disclosed no relevant financial relationships. 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.


Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.