Genetic regions linked to ACE inhibitor-induced angioedema ID’d

Researchers found a new locus that hadn't been linked to ACE inhibitor risk

Margarida Maia, PhD avatar

by Margarida Maia, PhD |

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A strand of DNA shows its double helix.

Three genetic regions were found to be associated with the risk of developing angioedema as a side effect of angiotensin-converting enzyme (ACE) inhibitors, according to a genome-wide association study (GWAS) of European and African-American people.

These include a new genetic locus that hadn’t been linked to the risk of ACE inhibitor-induced angioedema. While its exact function needs to be explored, the findings set the stage for developing better ways to prevent, diagnose, and treat the disease. The study, “Meta-analysis of ACE inhibitor–induced angioedema identifies novel risk locus,” was published in the Journal of Allergy and Clinical Immunology.

ACE inhibitors are used to treat high blood pressure. With them, however, blood vessels can become more permeable and leak fluid into nearby tissues. This can lead to rapid swelling under the skin and in mucous membranes, which is referred to as angioedema.

It’s thought that the risk of developing ACE inhibitor-induced angioedema is influenced by many factors. While genetic makeup can make a person more susceptible, the mechanisms leading up to disease are unclear, leading researchers to draw on data from 1,060 people with ACE inhibitor-induced angioedema and 77,799 controls of European ancestry.

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 Identifying risk loci for ACE inhibitor-induced angioedema

“The identification of the responsible genes will provide completely new insights here,” Markus Nöthen, MD, who directs the Institute of Human Genetics at the University Hospital Bonn and University of Bonn in Germany, said in a press release.

In a GWAS, researchers scan the genome — the entire set of DNA instructions found within cells — to look for variants that occur more frequently in people with a disease than in controls. This allows investigators to identify risk loci, or regions.

A total of three risk loci were identified, including a new risk locus in a region of chromosome 20 called 20q11.22. The other two loci, on chromosome 1 (1q24.2) and chromosome 14 (14q32.2), have been described previously.

“While two of the loci have already been described in previous studies, our study was the first to demonstrate a significant association for a new locus on chromosome 20,” said Andreas Forstner, MD, from the Institute of Human Genetics and the study’s corresponding author.

In the 20q11.22 locus, the lead single-nucleotide polymorphism, that is, the variant with the most significant link to ACE inhibitor-induced angioedema, was rs6060237, located close to a gene called EDEM2.

Once lead variants are identified, they can be used to search for nearby variants that could play a direct part in the disease. Using this approach, researchers identified 84 mapped genes across all three risk loci.

The top 50 included two with a known link to ACE inhibitor-induced angioedema: BDKRB2, which encodes the B2 receptor for bradykinin, a signaling molecule that causes blood vessels to widen and whose overproduction has been linked to some forms of angioedema, and F5, which encodes a clotting factor.

They also included KNG1, a gene linked to hereditary angioedema. Besides EDEM2, a “biologically plausible” candidate gene was PROCR, which codes for protein C receptor, which is involved in fibrinolysis, the process whereby blood clots are broken down when they’re no longer needed.

“We were able to identify several candidate genes at the three risk loci indicating that genetic changes in the bradykinin, coagulation and fibrinolysis signaling play a role in the development of this type of angioedema,” said Carina Mathey, a doctoral student at the Institute of Human Genetics and the study’s first author.

The lead variants at the three risk loci had similar effect sizes, that is, their link was as strong, in Europeans and African Americans.

“An exploratory cross-ancestry comparison implicated the relevance of the associated risk loci across diverse ancestries,” the researchers wrote.

“The identification of further risk loci through a continuous expansion of the GWAS study collectives in combination with functional analyses and the evaluation of lifestyle and environmental factors will make an important contribution to the development of new approaches for prevention, diagnostics and therapy in the long term,” said Bernhardt Sachs, MD, from the Federal Institute for Drugs and Medical Devices, Bonn.