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.
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.
The
less common gene variant identified in this study is related to a
decreased desire for alcohol. So, people who have this variant tend to
drink less than those without it, he said. In this study, the frequency
of the alcohol-decreasing variant among participants was 42 percent.
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 marks the fifth study in which Drs.
Mangelsdorf and Kliewer report that the hormone FGF21 directly affects
the central nervous system in mice.
A study published in December
2015 found that FGF21 works via the brain’s reward pathway to reduce
cravings for sugar and that FGF21 needed β-Klotho to function in that
signaling pathway. The current study indicates that FGF21 requires
β-Klotho in the signaling pathway that suppresses alcohol consumption,
he said.
In 2014, they reported that FGF21 acts on the brain to
cause weight loss. They also published two studies in 2013 reporting on
FGF21’s ability to regulate metabolism, circadian (body clock) behavior,
and female reproduction.
“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.”
Dr. Mangelsdorf is
one of six corresponding authors in the collaboration that involved more
than 120 researchers in the United States and Europe. One of the lead
authors on the study, Dr. Parkyong Song, is a postdoctoral researcher in
the Kliewer-Mangelsdorf laboratory.
Other corresponding authors
are at King’s College London; Friedrich-Alexander University
Erlangen-Nuremberg in Erlangen, Germany; the Framingham Heart Study,
Framingham, Mass.; The National Heart, Lung, and Blood Institute,
Bethesda, Md.; and Imperial College London.
Dr. Mangelsdorf serves
on the scientific advisory board of Metacrine, a biotech company that
seeks to develop anti-obesity drugs. For a complete list of all
researchers involved, their institutions, relevant disclosures, and
funding sources for this research, see the first page and appendix 2 of
the study, available from
PNAS.
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