A Gene That Knows When to Say When to Alcohol

Studies of alcohol consumption usually look at alcoholics and ask, “What goes wrong?” A new genome-wide study, however, looks at social drinkers and asks, “What goes right?” The answer, it turns out, is a gene variant that suppresses the desire to drink alcohol.

The study, conducted by the University of Texas (UT) Southwestern Medical Center and their European colleagues, found that the β-Klotho gene is linked to the regulation of social alcohol consumption. A variant of this gene that was seen in approximately 40% of the 105,000 people in this study is associated with a decreased desire to drink alcohol.

Details of the study appeared November 28 in the Proceedings of the National Academy of Sciences, in an article entitled, “KLB Is Associated with Alcohol Drinking, and Its Gene Product β-Klotho Is Necessary for FGF21 Regulation of Alcohol Preference.” The article describes how researchers compared the genetics of light and heavy social drinkers of European ancestry participating in nearly four dozen other large population studies worldwide. In addition to providing samples for genetic analysis, the participants answered questionnaires on their weekly drinking habits.

Heavy drinking was defined as more than 21 drinks per week for men and more than 14 drinks per week for women. Light drinking was considered to be 14 drinks or less per week for men and seven drinks or less per week for women. A “drink” was the equivalent of a small glass or wine or a half pint of beer.

“We conducted a genome-wide association meta-analysis and replication study…and identified β-Klotho (KLB) as a locus associated with alcohol consumption,” wrote the authors of the PNAS study. “β-Klotho is an obligate coreceptor for the hormone FGF21 [fibroblast growth factor 21], which is secreted from the liver and implicated in macronutrient preference in humans.”

The β-Klotho protein is an essential receptor component for the endocrine FGFs, FGF19 and FGF21. Using mouse models and pharmacologic administration of FGF21, the researchers showed that β-Klotho in the brain controls alcohol drinking.

In this part of the study, mice genetically unable to produce β-Klotho were offered a choice between water and alcohol. The genetically altered mice preferred alcohol, even when they were given the hormone FGF21, indicating that FGF21’s ability to suppress the preference for alcohol depends on the presence of β-Klotho.

“The gene in the current study seems to work via a feedback circuit that goes from the liver, which processes alcohol, to the brain, where β-Klotho and classic FGF21 receptors form a cellular machine, or receptor complex, which binds to the liver hormone FGF21 to signal the response to alcohol,” said David Mangelsdorf, Ph.D., a professor of molecular biology and pharmacology at UT Southwestern, and a corresponding author of the study.

“This is a hormone with some remarkable pharmacologic effects,” Dr. Mangelsdorf continued. “The current study suggests that the FGF21-β-Klotho pathway regulates alcohol consumption in humans and seems to point to a mechanism that we might be able to influence in order to reduce alcohol intake.”