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Sequencing Data Helps Elucidate Blood Pressure Ties to Rare Sodium Channel Mutations

NEW YORK – By identifying and analyzing the rare and-low frequency sodium channel mutations linked to blood pressure traits in thousands of people, a University of Pittsburgh-led team found signs of sodium channel contributions to blood pressure in kidney and other tissues.

"This study may help us someday identify people with specific, subtle genetic mutations that predispose them to a type of hypertension acting outside the kidneys," senior author Thomas Kleyman, a clinical pharmacology and cell biology researcher at the University of Pittsburgh, said in a statement. "Knowing that, we can better help that person control their blood pressure."

Bringing together whole-genome sequence and blood pressure phenotyping data for nearly 28,400 individuals from studies within the National Heart, Lung, and Blood Institute's Trans-Omics in Precision Medicine (TOPMed) Whole-Genome Sequencing Program or the Samoan Soifua Manuia Study, the researchers searched for variants associated with hypertension-related traits ranging from systolic blood pressure (SBP) or diastolic blood pressure (DBP) to pulse pressure (PP), mean arterial pressure (MAP), estimated glomerular filtration rate (eGFR), or stroke.

As the team reported in the journal Hypertension on Tuesday, results from variants association- and mutation burden-based analyses pointed to a preponderance of rare or low-frequency variants in epithelial sodium channel genes expressed in tissues within the kidney, along with "extrarenal" sodium channel subunits in tissues outside of the kidney.

In particular, the researchers found that rare or low-frequency variants in a SCNN1A gene coding for the alpha structural subunit appeared to influence DBP and MAP — traits that were also associated with rare variants in the beta subunit-coding gene SCNN1B. Meanwhile, low-frequency variants in the delta subunit gene SCNN1D variants seemed to be linked to SBP, DBP, PP, and MAP. Variants in the SCNN1B and SCNN1D genes also appeared to influence estimated glomerular filtration rate, they reported.

The findings complement prior studies linking rare sodium channel mutations to Mendelian conditions such as Liddle syndrome that impact blood pressure, the team explained, noting that the current study did not uncover variants associated with stroke or common variants with ties to blood pressure.

With a series of follow-up experiments — including RNA sequencing analyses focused on SCNN1D expression in human monocyte cells from 11 individuals with normal or increased sodium levels — the researchers tracked the activity of such epithelial sodium channel subtype genes, uncovering non-renal expression of the subtype-coding gene SCNN1D, which appears to be expressed far more modestly within the kidney itself.

"Previously there had been some hints that mutations to salt-processing channels outside the kidneys affected blood pressure," first author Brandon Blobner, a gastroenterology, hepatology, and nutrition researcher at the University of Pittsburgh, said in a statement, "but it would have been impossible to confirm the mechanism without the massive genetics databases that we had access to through cross-disciplinary partnerships."