- A variation in the β-Klotho gene is linked to the regulation of social alcohol consumption.
- The gene variation includes a complex of the β-Klotho gene and Fibroblast growth factor 21 (FFG21),a liver hormone that suppresses sugar craving.
- FGF21 needs β-Klotho to subdue the craving for alcohol.
"The findings are based on the largest genome-wide association meta-analysis and replication study to date mapping and comparing the genetics - the DNA - of more than 105,000 light and heavy social drinkers," said Dr. David Mangelsdorf, Chair of Pharmacology at UT Southwestern and a corresponding author of the study.
‘β-Klotho gene codes for the protein β-Klotho, which forms a receptor complex in the brain with receptors for FGF21, a hormone produced in the liver and shuns alcohol craving.’
Advertisement"The study identified a variation in the β-Klotho gene linked to the regulation of social alcohol consumption. The less frequent variant - seen in approximately 40 percent of the people in this study - is associated with a decreased desire to drink alcohol," he said.
Dr. Mangelsdorf runs a laboratory with Dr. Steven Kliewer, another corresponding author of the study published online in the Proceedings of the National Academy of Sciences .
"Excessive alcohol consumption is a major public health problem worldwide, causing more than 3 million deaths per year," said Dr. Kliewer, a Professor of Molecular Biology and Pharmacology who holds the Nancy B. and Jake L. Hamon Distinguished Chair in Basic Cancer Research.
The European research group knew that the UT Southwestern team had worked on β-Klotho and the liver hormone fibroblast growth factor 21 (FGF21) that binds to the β-Klotho-FGF21 receptor complex.
"They asked us to conduct experiments in mice to better understand the role of β-Klotho in alcohol drinking behavior," Dr. Mangelsdorf said. "The β-Klotho gene directs the production of the β-Klotho protein that forms part of a receptor complex in the brain."
This study of genetic influences on brain function affecting drinking behavior indicates the promise of pharmacogenetics, a field of precision medicine that the National Institutes of Health (NIH) describes as the study of how genes affect responses to drugs.
Like many complex traits, the genetic influences on brain functions affecting drinking behavior were thought to be so small that it would be necessary to study large numbers of people in order to detect those genetic variations, said Dr. Mangelsdorf, also Professor of Biochemistry and a Howard Hughes Medical Institute Investigator.
The β-Klotho gene codes for the protein β-Klotho, which forms a receptor complex in the central nervous system (the brain and spinal cord) with classic receptors for FGF21, a hormone produced in the liver.
"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," Dr. Mangelsdorf said.
To better understand how the gene works, the Kliewer-Mangelsdorf lab offered mice genetically unable to produce β-Klotho 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, he said.
"This is a hormone with some remarkable pharmacologic effects," Dr. Mangelsdorf said. "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."