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Meta-analysis Reveals New Blood Pressure Loci

NEW YORK (GenomeWeb News) – In a study appearing online today in the American Journal of Human Genetics, an international research team described 11 new blood pressure-linked loci identified through a gene-focused meta-analysis of genome-wide association study data on more than 150,000 individuals of European ancestry.

By bringing together genotyping data on more than 156,000 individuals for their meta-analysis and replication studies, the researchers narrowed in on 27 known and 11 new sites in the genome that showed ties to systolic blood pressure, diastolic blood pressure, mean arterial pressure, and/or pulse pressure.

The new loci spanned some 31 genes, including 10 sequences that code for proteins targeted by existing small molecule drug candidates, study authors noted. Based on such findings, they suspect that genes in these regions — and network connections between them — could offer clues to coming up with targeted blood pressure treatments.

"The fact that most of these new gene signals are 'druggable' targets offers the possibility of expedited pharmaceutical development of therapeutics for high blood pressure, a serious risk factor for cardiovascular diseases," co-senior author Brendan Keating, a genetics researcher affiliated with the University of Philadelphia and the Children's Hospital of Philadelphia, said in a statement.

"Some of the protein targets already are targets of existing drugs for other diseases," Keating added, "while others are the focus of drugs currently in early-phase clinical trials or under preclinical development."

Although many past GWAS, admixture, and meta-analysis studies have tackled the genetics of blood pressure traits, he and his co-authors explained, common variants identified so far still explain relatively little of the heritable variation associated with such features.

For their own effort to flesh out this set of risk variants, the researchers did a gene-centric meta-analysis that tapped data at more than 52,000 SNPs assessed with Illumina arrays that span thousands of genes implicated in some aspect of cardiovascular disease or related traits.

When the team looked at these variants in 87,736 individuals of European descent with known blood pressure traits, it identified 17 SNPs with apparent ties to systolic blood pressure, diastolic blood pressure, mean arterial pressure, and/or pulse pressure.

After replicating promising results from the discovery meta-analysis using samples from 68,386 more individuals from the same population, the researchers were left with 11 new SNPs showing significant ties to one or more of the blood pressure measures considered.

Of the 32 known blood pressure loci covered by arrays used in the new analysis, the team determined that 27 had at least nominal blood pressure associations in the directions previously described.

To their search for common gene-based variants contributing to blood pressure, the researchers also added bioinformatics and pharmacological analyses aimed at interpreting and applying the new genetic findings.

For instance, their results suggest that at least some of the variants detected in the study are linked to expression quantitative trait loci influencing the expression of suspected blood pressure contributor genes.

On the drug candidate side, the group saw two genes within blood pressure-associated loci that are targeted by existing treatments for blood pressure or other conditions. Another 10 genes from within the associated sites encode proteins suspected to respond to small molecule drugs based on information from past studies and/or drug databases.

"It is particularly interesting that most of the genes within the associations are suitable candidates for existing drugs or pre-clinical compounds," Keating and colleagues concluded. "These new observations will help to improve our knowledge on [blood pressure] and related mechanisms."

Keating told GenomeWeb Daily News that his group and their collaborators do not currently have plans to pursue clinical trials or drug development related to findings from the study. "Part of the value of doing these studies is that we can put this information out to other people who can look at it and work on it," he said.

For their part, the study's authors are focused on delving into potential blood pressure contributions made by genes within blood pressure-associated loci. They also hope to find still more sites in the genome that can impact blood pressure profiles in individuals from European and other populations under various conditions.

"We think there are still even more loci to be discovered," Keating said. "Blood pressure is one of the weakest in terms of heritability that's been explained … so some of these [risk loci] may be perturbed in specific environmental circumstances."