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Hundreds of Hypertension-Related Effector Genes Identified in Genetic Fine-Mapping Study

NEW YORK — An international team of researchers has identified hundreds of candidate effector genes involved in hypertension, paving the way for functional validation studies and the discovery of new drug targets.

Hypertension affects over 1 billion people globally and is one of the most critical risk factors for cardiovascular disease, leading to around 10 million annual deaths.

In a paper published in the American Journal of Human Genetics on Thursday, investigators led by Andrew Morris at the University of Manchester and Patricia Munroe at Queen Mary University of London used genetic fine mapping of SNVs and multiomics to identify causal variants and candidate effector genes for systolic blood pressure, diastolic blood pressure, and pulse pressure.

While genome-wide association studies had previously identified around 1,000 blood pressure-associated loci, effector genes and relevant biological processes had yet to be uncovered, the authors wrote.

For their study, the researchers used summary statistics from previously reported GWAS meta-analyses of blood pressure traits in almost 758,000 individuals of European ancestry from the International Consortium of Blood Pressure and the UK Biobank.

They considered 650 genomic regions encompassing previously reported SNVs related to blood pressure, narrowing in on 606 loci with leads SNVs that had genome-wide significance for at least one blood pressure trait. They then conducted cross-trait conditional analyses, which generated 1,850 signals for at least one blood pressure trait, including 532 signals associated with at least two traits and 84 associated with all three.

Using a range of genetic fine-mapping techniques in various tissues, coupled with tissue-specific chromatin segmentation and colocalization assays, they were able to shortlist 436 plausible effector genes. These included genes encoding angiotensin and angiotensin-converting enzyme, sodium/potassium-transporting ATPase subunit beta-1 (ATP1B1), and rho GTPase-activating protein 42 (ARHGAP42). They added other possible but less well-characterized genes identified through eQTL analysis, including CDH13, FES, FGF5, and JPH2. Loci and signals within the same genomic regions affected different genes in different tissue types, they wrote.

Subsequent gene enrichment analysis helped pinpoint some of the pathways associated with all three blood pressure traits, including circulatory system development, embryonic development, tube development, regulation of cell differentiation, urogenital system development, and renal system development, all of which have been previously highlighted as important in blood pressure control, according to the researchers.

To determine which effector gene candidates could become potential drug targets, they compared them to a published list of protein-coding genes in the "druggable genome." For diastolic blood pressure, they found several candidate effector genes encoding proteins already used as targets for anti-hypertensive medications. Overall, 13 percent of the blood pressure genes were found to be drug targets, they wrote.

They also shortlisted several other effector genes whose protein products are targets of existing drugs and could potentially become targets for hypertension. They included AKR1B1 (aldo-keto reductase family 1 member B), a target of aldose reductase inhibitors that has been investigated for use in diabetes and also has effects on blood pressure, they wrote. Furthermore, they identified drug repositioning opportunities, in particular, an enrichment of the blood pressure effector genes in gene sets for cardiovascular and renal conditions.

Highlighting the study's limitations, the authors wrote that the GWAS dataset lacked population diversity, as it only included people of European ancestry.