big impact on blood pressure
Yale researchers have discovered that rare genetic variants can be associated
with a dramatically lower risk of developing high blood pressure in the general
population. — By Bill Hathaway
T H I S
The study was published in the April 6 issue of the journal Nature Genetics.
The insight that rare mutations may collectively play a large part in the development
of common yet complex diseases such as hypertension also has implications for
the diagnosis and treatment of diseases such as diabetes and schizophrenia.
The team of researchers was led by Richard Lifton, chair of the Department of
Genetics and Sterling Professor of Genetics and Internal Medicine at Yale, and
Daniel Levy, director of the National Heart, Lung and Blood Institute’s
Framingham Heart Study.
The scientists analyzed DNA samples from 3,125 people who participated in the
Framingham Heart Study, a long-running epidemiology survey that has led to a
treasure trove of information about the causes of heart disease.
They decided to study the health impact of three genes regulating the processing
of salt in the kidney — each of which is known to cause dangerously low
blood pressure levels when inherited with two defective copies (one from each
parent). The researchers speculated that people who carry only one defective
copy might be less prone to hypertension.
Lifton’s group found that 2% of the subjects carried one defective copy of one of the three genes. These individuals
in general had lower blood pressure and a 60% lower risk of developing hypertension
by the time they were 60 than the general population.
A major question in the field of many chronic diseases has been whether the risk
of developing a disease is more closely linked to common or rare mutations. Recent studies have shown that for many diseases, common genetic variants can only explain a small fraction of an individual’s
risk of developing a particular condition. In the case of high blood pressure,
for instance, large genome-wide studies have thus far found no common variants
that are associated with the risk of developing hypertension.
So, scientists like Lifton and his lab members Weizhen Ji and Jia Nee Foo have
begun to search for the many rare mutations that might have a larger impact on
the risk of inherited diseases on smaller groups of people.
“Collectively, common variants have explained a small fraction of the risk
of most diseases in the population, as we would expect from the effects of natural
selection,” Lifton says. “The question this leaves open is whether
many rare variations in genes will collectively account for a large influence
on common disease.”
Lifton said the new study underscores the importance of sequencing the genome
of many individuals in order to discover disease-causing mutations.
For instance, previous genetic studies of hundreds of families with severely
low blood pressure enabled his team to identify the gene mutations used in the
study. And one of the genes, ROMK, has turned out to be a particularly promising
target for new high blood pressure therapy.
Eventually, scientists may find dozens of genes in which rare mutations individually
account for a low percentage of common diseases among individuals, but may collectively
account for the burden of common chronic diseases, Lifton says.
Added Levy, “We may have to march down the field from gene to gene to identify other genes where rare variants
are contributing to blood pressure variations.”
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