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Untangling the causes of high blood pressure

Researchers discover an unexpected gene mutation associated with high blood pressure


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Untangling the causes of high blood pressure

Nearly half of American adults have high blood pressure, according to the Centers for Disease Control and Prevention’s most recent polling data. Only 24 percent of adults with hypertension, defined as blood pressure greater than 140/90 mm Hg, have success using medication to return their blood pressure to normal levels.

Scientists at the University of Pittsburgh recently solved one piece of the puzzle with their discovery of a rare gene mutation that contributes to hypertension. Experts in the field have differing perspectives on how the discovery could affect treatment for high blood pressure, which can be caused by lifestyle or genetics.

The study, published on Oct. 4 in the journal Hypertension, examined mutations in the four genes that encode subunits of the body’s epithelial sodium, or salt-processing, channel. Researchers already knew that mutations in three of those genes (alpha, beta, and gamma) found in kidney cells caused high blood pressure. But mutations in a gene outside the kidneys (delta), were previously unknown to influence blood pressure.

“Our findings were entirely unexpected,” chief author Brandon Michael Blobner said. “Previously there had been some hints that mutations to salt-processing channels outside the kidneys affected blood pressure, but it would have been impossible to confirm without the massive genetic databases we had access to through cross-disciplinary partnerships.”

Blobner teamed up with Ryan Minster, assistant professor of human genetics at the University of Pittsburgh’s School of Public Health. They accessed genomic sequences and blood pressure records from about 28,000 people participating in either the Trans-Omics in Precision Medicine (TOPMed) Whole-Genome Sequencing Project or the Samoan Good Health Study.

Senior author Thomas Kleyman, chief of the renal-electrolyte division at the University of Pittsburgh Medical Center, said the study’s findings indicate the need for a more holistic approach to developing effective hypertension medications.

Michelle Gumz, associate director of the Center for Integrative Cardiovascular and Metabolic Diseases at the University of Florida, agrees with Kleyman. She explained that blood pressure researchers tend to study only one of three systems—the kidneys, blood vessels, or brain. “We tend to be very reductionist in our research approaches,” Gumz said. “But when you think about a human walking around with high blood pressure, [it] could be all kinds of systems in that person’s body that are contributing to this.”

Eric Hussar, a family physician in Lancaster County and Pennsylvania state director of the American Academy of Medical Ethics, thinks the discovery of the delta gene mutation could shift how doctors treat hypertension. “It gives [doctors] one extra target,” he said.

But Hussar said the finding’s significance can’t be assessed until we know how many people have a delta mutation. If a low percentage of the population has it, say 0.01 percent, Hussar predicts the development of an “orphan drug.” Orphan drugs treat rare diseases that would not be profitable without government assistance.

Hussar noted additional barriers to the development of clinical treatment, including the need for a test to screen for the delta mutation in hypertensive patients, which he predicted would be expensive and require buy-in from insurance companies.

He also cautioned that even if those barriers were removed, there’s still the possibility of a medication that lowers blood pressure without decreasing the risk of the disease associated with hypertension, such as stroke, heart attack, or kidney disease. “If the only point of lowering the blood pressure is to make the number look better, I haven’t actually done any good for my patient,” he said.

Gumz has a more optimistic approach to the study’s findings. She explained that while researchers understand what the epithelial sodium channel (ENaC) does inside the human kidney, they don’t have a good grasp on what it does elsewhere in the body. By showing that the ENaC channel plays a role in immune cells, this study reveals an exciting new role for the ENaC channel. “This is really getting to the mechanism of how the immune system regulates blood pressure,” she said.

Screening tools for rare genetic mutations already exist, Gumz suggested, in the form of DNA kits. Companies such as 23andMe offer test kits that provide individuals with genetic risk data for diseases that include high blood pressure. Patients could bring this information to their doctors, which could aid in tailoring their blood pressure medications. For example, amiloride, a diuretic drug that works to lower blood pressure by inhibiting ENaC, could work as a targeted drug for someone with a known mutation in this channel.


Heather Frank

Heather is a science correspondent for WORLD. She is a graduate of World Journalism Institute, the University of Maryland, and Carnegie Mellon University. She has worked in both food and chemical product development, and currently works as a research chemist. Heather resides with her family in Pittsburgh, Pa.

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