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New Blood Pressure, Hypertension Loci Identified Through Large Analyses

NEW YORK (GenomeWeb) – A trio of studies published today in Nature Genetics described new genetic loci linked to blood pressure and hypertension in individuals from several human populations.

An international team led by investigators in the UK, the US, and the Netherlands first brought together SNP genotyping data for nearly 193,000 individuals enrolled through dozens of prior studies, searching for common and lower frequency variants contributing to traits such as systolic blood pressure, diastolic blood pressure, pulse pressure, and hypertension.

Analyses of those individuals led to 46 sites in the genome with apparent ties to blood pressure-related traits in European and South Asian populations and another five loci linked to at least one of these features in European individuals.

After a replication stage of their study that included data for another 155,063 or so individuals, the researchers did a meta-analysis involving roughly 350,000 individuals from European, South Asian, Hispanic, and African populations, focusing on 81 candidate SNPs. Together, these analyses led to 30 previously undetected loci that were each associated with one or more blood pressure- or hypertension-related trait — including loci containing SNPs implicated in cardiovascular traits or conditions in the past.

The set of blood pressure-associated sites also contained a handful of rare missense variants affecting the RBM47, COL21A1, and RRAS genes, the study's authors noted, "complementing and extending the previous discovery and characterization of variants underlying rare Mendelian disorders of blood pressure regulation."

In another Nature Genetics paper, researchers from the National Institutes of Health, Brigham and Women's Hospital, and elsewhere did their own blood pressure-focused meta-analysis centered on protein-coding sequences assessed using the Exome Chip array.

Starting with a discovery group of almost 150,000 individuals from European, African American, and Hispanic populations enrolled through the CHARGE consortium, the team narrowed in on 15 new candidate loci with potential blood pressure ties across ancestry groups and detected apparent associations at more than three dozen loci linked to blood pressure in the past.

Folding in existing exome and blood pressure trait data for nearly 181,000 more individuals, the researcher replicated 11 of the 15 candidate loci and uncovered 20 new loci for the meta-analysis stage of the study. Again, the associated loci included low frequency variants at three sites — this time, in and around the NPR1, SVEP1, and PTPMT1 genes.

In addition to genes involved in cardiovascular pathways, that analysis highlighted the potential importance of variants affecting genes better known for their roles in things like diabetes, immune disease, vascular development, or kidney function.

"The overlap of these genetic variants with immunologic and metabolic diseases suggests that there may be common underlying causes for elevated blood pressure and other metabolic risk factors," co-corresponding author Daniel Chasman, a genetics researcher affiliated with Brigham and Women's Hospital and Harvard Medical School, said in a statement. "This may also serve as a starting point for finding therapies that can more broadly treat hypertension to reduce cardiovascular risk."

For the third study, some members of the same team considered the genetic architecture behind blood pressure-related traits in the context of other cardiovascular and metabolic traits. The researchers combined data for more than 109,000 individuals who were directly genotyped with the Cardio-Metabochip array and 92,433 individuals genotyped on genome-wide arrays who had their variants imputed at Cardio-Metabochip-covered sites.

Following validation and meta-analyses that included 141,000 other individuals, they identified 17 new blood pressure-associated loci and dozens more sites associated with these traits in prior studies.

Broad Institute researcher and co-corresponding author Christopher Newton-Cheh noted in a statement that "[e]ven with hundreds of thousands of people studied and over 100 blood pressure genes identified to date, we estimate that there are still hundreds more to find. Only when we can study millions of people — particularly people of non-European ancestry who have been underrepresented in past studies — will we have a chance at finding them all."