Stroke genetics: HTRA1-independent mechanisms increase risk, study shows

Cardiovascular diseases, including stroke and coronary artery disease, are among the leading causes of death worldwide. Classic risk factors include age, personal lifestyle and pre-existing conditions, but genetic predisposition also plays a role.

“Genome-wide association studies have identified multiple genes that influence the risk of stroke and cardiovascular disease,” says LMU Professor Martin Dichgans. “They have also shown that genetic information can be used to discover potential drug targets for targeted therapies.”

LMU researchers have discovered two independent ways in which genetic variants increase the risk of cardiovascular disease. The study is published in the journal Cardiovascular Nature Research.

Director of the Stroke and Dementia Research Institute at LMU University Hospital and scientist in the SyNergy Excellence Group, Dichgans is the principal investigator of the study, which undertook an in-depth investigation of the HTRA1 gene. The gene encodes a protease – an enzyme that has a regulatory effect on the extracellular matrix.

“HTRA1 has proven to be a risk gene for various disorders, including stroke and cerebral small vessel disease,” explains the researcher. People who inherit specific gene variants are more likely to suffer from such pain. However, the mechanisms underlying this increased risk were previously poorly understood.

Loss of function and decreased concentration

In the new study, researchers have filled an important part of this knowledge gap. By integrating clinical and genetic information from large biobanks with results from targeted biochemical experiments, they investigated the effects of 78 HTRA1 variants on protease enzymatic function.

“We were able to demonstrate two independent mechanisms by which rare and common gene variants influence cardiovascular risk,” summarizes postdoctoral researcher Nathalie Beaufort, one of the lead authors.

While some rare variants in HTRA1 reduce protease activity, other more common variants lead to reduced blood concentrations of the enzyme. “Our results indicate that HTRA1 activity and HTRA1 concentration should be considered in future clinical applications,” says Beaufort.

“Both mechanisms increase the risk of stroke and coronary artery disease,” adds postdoctoral researcher Rainer Malik, another lead author of the study. “However, they are independent of each other and have different effects on different phenotypes.”

Rare gene variants leading to loss of protease activity, for example, are also associated with certain skeletal traits. In contrast, the common variant – which affects the concentration of the protein – reduces the risk of migraines and some degenerative eye diseases.

It is not only cardiovascular risk that is affected

The new findings will also influence future therapeutic strategies. In principle, cardiovascular risk can be decreased either by restoring HTRA1 activity or by increasing HTRA1 concentration.

“As our study shows, however, an increase in HTRA1 concentration leads to a higher risk of age-related macular degeneration and other retinal disorders,” says Malik. This highlights the need to develop organ- or cell-type-specific therapies.

“Until now, scientists have viewed the relationship between HTRA1 and disease in binary terms,” ​​notes Dichgans. “Our results demonstrate the importance of considering HTRA1 activity as a persistent phenotype.”

In the future, researchers aim to discover how gene variants affect different cell types and tissues.