Rare genetic mutations have led scientists to surprising blood pressure discoveries

The kidneys are often the unsung heroes of maintaining healthy blood pressure, filtering 180 liters of fluid and a pound of salt a day to maintain blood pressure levels
.
But new research by geneticists and nephrologists at the University of Pittsburgh shows that surprisingly, a cellular channel outside the kidney plays an important role
in controlling blood pressure.

The findings, published in the journal Hypertension, provide a promising new target for clinical trials to test the potential of
existing drugs to lower blood pressure.

"Our findings were completely unexpected," said
Dr.
Brandon Michael Blobner.
He did this research at Pitt University as part of his doctoral thesis and is now a bioinformatics scientist
at BlueSphere Bio in Pittsburgh.
"There have been some indications in the past that mutations in the extrarenal salt processing channels affect blood pressure, but without the extensive genetic database we have obtained through interdisciplinary collaboration, it would not have been possible to confirm this mechanism
.
"

Nearly half of U.
S.
adults have high blood pressure, which is linked to chronic kidney disease and stroke, with a particularly high
percentage of black patients.
According to the U.
S.
Centers for Disease Control and Prevention, only one in four people has high blood pressure under control, making it one of
the biggest public health problems in the United States.

To some extent, high blood pressure is caused by abnormal levels of fluid and salt in the body, putting pressure on the artery walls and damaging blood vessels and organs
.

The Pitt University study focused on channels that the cell membranes of certain cells use to regulate fluid volume, based on the amount of sodium in the
cells.
Blobner was curious to see if mutations in the gene encoding the channel subsystem affected blood pressure
.

Encouraged by Thomas Kleyman, M.
D.
, the Sheldon Adler Professor of Medicine at Pitt University, Blobner teamed up with Ryan Minster, Ph.
D.
, assistant professor of human genetics at the Pitt School of Public Health, to build a dataset containing genome sequences and blood pressure records involving more than 28,000 people involved in the Precision Medicine (TOPMed) whole genome sequencing project or the Somoan Soifua Manuia study
。

"One of the really exciting things about this project for me is that it's so targeted and hypothesis-driven
," Minster said.
"Often in these big genomics projects, where we're more agnostic — casting a wide net — it can take decades to validate a discovery
.
" The project made major discoveries
very quickly.
”

Scientists have known that rare mutations in the genes encoding channels α, β and γ sub-subsystems (all three of which are found in kidney cells) can cause dangerous extreme blood pressure levels
.
But when scientists looked at more subtle mutations, they found that a fourth sub—δ—affects blood pressure
.
Importantly, δ
are found in immune cells outside the kidneys, as well as in the lungs, heart, and colon.

"I'm a nephrologist and I've dedicated my entire career to understanding the kidneys and their role
in maintaining sodium levels to regulate blood pressure," Kleiman said.
Kleiman is also head of UPMC's Renal Electrolytes Division and senior author
of the study.
"But our research over the past few years has broadened my focus
.
This study shows that we must go beyond the kidneys and better target antihypertensive drugs
.
”

One of the dangers of some blood pressure medications is that they can cause high potassium levels, which can be fatal
.
But this problem is related to
low kidney function.
Theoretically, if a person's high blood pressure is due to an imbalance of fluids and salts caused by malfunctions in cell channels outside the kidneys, then this drug may be an effective treatment, reducing the risk of
high potassium levels.

"One of the things we're particularly interested in at UPMC is targeted therapy — you want to get the right drug to the right person
at the right time," Kleiman said.
"This study may help us one day identify people with specific, subtle genetic mutations that would make them more susceptible to a type of high blood pressure
that acts outside of the kidneys.
" Knowing this, we can better help patients control their blood pressure
.
”