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Kidney Omics Study Sheds Light on Blood Pressure Mechanisms

NEW YORK – An international team led by investigators in the UK has untangled blood pressure-related mechanisms and related drug targets in the kidney, combining insights from previous genome-wide association studies of hypertension with new genotyping, expression, gene splicing, and DNA methylation profiles.

"Using variants implicated in these analyses, we … demonstrate effects of BP on several kidney outcomes known as complications of human hypertension," senior and corresponding author Maciej Tomaszewski, a researcher affiliated with the University of Manchester, the Manchester Heart Centre, and Manchester Academic Health Science Centre, and his co-authors wrote. They added that these and other findings "show that some kidney gene targets of BP-GWAS variants are druggable, and we highlight those of potential relevance to treatment of hypertension."

As they reported in Nature Genetics on Thursday, the researchers brought together genome sequencing data, array-based genotyping data, RNA sequencing data, and array-based DNA methylation profiles of kidney samples from a total of 430 individuals of European descent to get a look at genomic, transcriptomic, epigenomic, and splicing patterns in the kidney. When they analyzed that data alongside hypertension-associated SNPs from prior BP-GWAS, they found that more than half of the risk variants — 479 SNPs — targeted some 1,038 genes expressed in the kidney.

Findings from subsequent colocalization and Mendelian randomization analyses underscored kidney contributions to blood pressure regulation more broadly, the authors explained, pointing to at least 179 kidney genes that appear be causally associated with BP. A subset of those genes has been implicated in hypertension in the past, they noted, while new causal candidate genes turned up in seemingly unrelated pathways.

"Our study provides a very powerful example of how human tissue biobanks can help to bridge the gap between DNA and the disease (hypertension) through utilizing state-of-the-art methodology and newest technological advances," Tomaszewski explained in an email. "Most importantly, they provide evidence for the key role of the kidney as the mediator of the genetic predisposition to high blood pressure."

In addition to analyses aimed at uncovering risk variants influencing the expression, splicing, or methylation of kidney genes, the team searched for kidney gene targets of hypertension risk variants that may respond to drug treatments — a search that led to just over four dozen blood pressure-related kidney genes that may be targeted by 210 licensed drugs.

"By exploring the effects of BP-associated genetic variants on molecular targets operating at the intersection of the kidney transcriptome and the epigenome, our data help to bridge the existing knowledge gap between the 'sequence' (discoveries from GWAS) and 'consequence' (human hypertension)," the authors wrote.

They concluded that "elucidating the molecular mechanisms of hypertension embedded in the kidney, our study will ultimately lead to advancement in patient-centered diagnostic accuracy in hypertension and new targeted strategies to BP lowering, thereby accelerating progress in precision medicine."

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