Liver-brain pathway may regulate alcohol consumption – Medical Xpress

 In Health
3D-illustration of a human liver with blood vessels (red and blue) and bile duct (green) Source: Prof. Dr. Hans-Peter Meinzer, Deutsches Krebsforschungszentrum

In the largest study of its kind, UT Southwestern Medical Center researchers and colleagues in Europe identified a gene variant that suppresses the desire to drink 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.

“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 today in the Proceedings of the National Academy of Sciences (PNAS).

“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. “Much of the research on alcohol consumption has focused on addiction. However, the overall burden of alcohol-associated disease reflects the total amount of alcohol consumed, not just addiction.”

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.”

The PNAS study could lead to development of drugs to regulate alcohol consumption – possibly even in those with drinking problems. Alcoholics were not part of the current study, however.

A shift from heavy to moderate social drinking could have major public health benefits, such as reduced cardiovascular disease risk. Increased alcohol consumption is linked to two heart disease risk factors in particular: high blood pressure and obesity, according to the American Heart Association.

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. Dr. Mangelsdorf holds the Alfred G. Gilman Distinguished Chair in Pharmacology, and the Raymond and Ellen Willie Distinguished Chair in Molecular Neuropharmacology in Honor of Harold B. Crasilneck, Ph.D.

The study 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.

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