Medical News: Addictions
Gene Variant Linked to Alcohol Consumption
By Michael Smith, North American Correspondent, MedPage Today
Published: November 20, 2008
Reviewed by Zalman S. Agus, MD; Emeritus Professor
University of Pennsylvania School of Medicine. Earn CME/CE credit
for reading medical news
CHARLOTTESVILLE, Va., Nov. 20 -- Variation in the gene for the serotonin transporter appears to be linked to how much some alcoholics drink, researchers here said. Action Points
Explain to interested patients that the serotonin system plays an important role in alcohol preference and consumption, although details are not completely understood.
Note that this study found a link -- among alcohol-dependent people -- between genetic variation in the gene for the serotonin transporter and the propensity for heavy drinking.
In alcohol-dependent people of European descent, a single-letter change in the SLC6A4 gene was associated with significantly heavier drinking, according to Ming Li, Ph.D., of the University of Virginia and colleagues.
And in laboratory experiments, cells with the variant produced significantly less SLC6A4 mRNA and transporter protein, the researchers reported online in Alcoholism: Clinical & Experimental Research.
The serotonin system plays an important role in alcohol preference and consumption, the researchers said, and the serotonin transporter gene was thought to regulate a person's propensity for severe drinking.
"Acute drinking increases serotonin release and signaling in brain regions involved in controlling consumption of alcohol, while chronic drinking reduces serotonergic function, leading to a serotonin-deficient state," Dr. Li said in a statement. "One hypothesis is that alcoholics drink to alleviate this serotonin-deficient state."
But given that hypothesis, it's possible that functional variations in the serotonin transporter gene would play a role in how much alcoholics drink, the researcher said.
To help clarify the issue, Dr. Li and colleagues studied six different single nucleotide polymorphisms (SNPs) in a cohort of 275 alcoholics who were seeking treatment, including 165 Caucasians and 110 Hispanics.
The researchers measured intensity of drinking by counting drinks per drinking day in the previous 90 days -- defined as the average number of drinks in a day when a volunteer was consuming alcohol.
They also measured the average number of drinks per day in the previous 90 days.
Of the six SNPs, only one -- dubbed rs1042173 -- showed any association with the intensity of drinking, the researchers reported, and that was only seen in Caucasians.
Caucasians having two copies of the T allele of rs1042173 consumed an average of 11.17 drinks per drinking day, compared with an average of 8.58 for people with one copy of the G allele. The difference was significant at P=0.003.
Because estrogen has been shown to modulate the synthesis, release, and metabolism of serotonin, the researchers repeated the analysis excluding the female volunteers and found no difference, implying that sex plays no role in the association.
On the other hand, the researchers found no evidence that the variant was associated with drinking intensity among Hispanic participants, which suggests "the possibility of differential regulation of gene expression by ethnic group."
To see whether the variation has a functional effect on serotonin transporter expression, the researchers transfected the T and G alleles into experimental cells and measured the presence both of the gene variant and the transporter protein.
In the experiments, cells transfected with the G allele always produced at least 50% more SLC6A4 mRNA than cells with two copies of the T allele, an effect that was significant at P<0.0001.
At the same time, the G allele led to significantly higher levels of the transporter protein (at P=0.005), the researchers said.
"Some individuals may possess inherent risk factors for more intense drinking than others," Dr. Li said, "making them more vulnerable to complications arising from heavy drinking."
One implication of the finding, Dr. Li said, is that the variation might help predict treatment outcomes of different agents that target the serotonin system.
The study begins to fulfill the promise that modern genomics might lead to more personalized approaches to alcohol treatment, said Robert Philibert, M.D., Ph.D., of the University of Iowa, who was not part of the study.
"An implicit assumption of the Human Genome Project was that deciphering of the human genome would lead to better treatment," Dr. Philibert said in a statement.
"By and large, that promise has not yet been realized -- particularly for those with psychiatric illnesses," he said.
But the work of Dr. Li and colleagues, he said, links a genetic marker with quantitative clinical measures and "further connects the laboratory benchtop with the patient."
They pointed out that a "caveat to our results is that our cohort was a popu-
lation of treatment-seeking, alcohol-dependent individuals who were motivated to decrease or cease their alcohol consumption. Therefore, this cohort may be more motivated and perhaps less dense in drinking pathophysiology compared with alcohol-dependent individuals derived from community samples."
The study was supported by the National Institute on Alcohol Abuse and Alcoholism, and the National Institute on Drug Abuse.
Dr. Li did not report any conflicts.
Primary source: Alcoholism: Clinical & Experimental Research
Seneviratne C, et al "Characterization of a functional polymorphism in the 3´ UTR of SLC6A4 and its association with drinking intensity" ACER 2008