Stroke genetics: independent HTRA1 mechanisms increase risk
Researchers have discovered two independent ways by which genetic variants increase the risk of cardiovascular diseases
cardiovascular diseases, including stroke and coronary artery disease are among the leading causes of death worldwide. Classical risk factors include age, personal lifestyle, and pre-existing conditions, but genetic predisposition also plays a role. “Large-scale 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.”
Director of the Institute for Stroke and Dementia Research at LMU University Hospital and scientist in the SyNergy Cluster of Excellence, Dichgans is lead investigator of a study which has just been published in the journal Nature Cardiovascular Research. The study undertook a deep investigation of the gene HTRA1, which encodes a protease – an enzyme that has a regulating effect on the extracellular matrix. “HTRA1 has proven to be a risk gene for various disorders, including stroke and diseases of the cerebral small vessels,” explains the stroke and dementia researcher. People who inherit specific variants of the gene are considerably more likely to suffer from such afflictions. However, the mechanisms underlying this increased risk were insufficiently understood before.
Loss of function and reduced concentration
In the new study, the researchers have filled an important part of this knowledge gap. Integrating clinical and genetic information from from large biobanks with results from targeted biochemical experiments, they investigated the effects of 78 HTRA1 variants on the enzymatic function of the protease. “We were able to demonstrate two independent mechanisms by which rare and common variants of the gene affect cardiovascular risk,” summarizes postdoctoral researcher Nathalie Beaufort, one of the lead authors. While certain rare variants in HTRA1 reduce the activity of the protease, other more common variants lead to reduced concentration of the enzyme in the blood. “Our results indicate that both HTRA1 activity and HTRA1 concentration must be taken into account 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.” The rare gene variants that lead to loss of protease activity, for example, are additionally associated with certain skeletal traits. By contrast, the common variant – affecting protein concentration – reduces the risk of migraines and certain degenerative eye diseases.
Not only cardiovascular risk is influenced
The new findings will also influence future therapeutic strategies. In principle, cardiovascular risk could be lowered by either restoring HTRA1 activity or increasing HTRA1 concentration. “As our study shows, however, an increase in HTRA1 concentration leads to an elevated risk of age-related macular degeneration and other retinal disorders,” says Malik. This highlights the need to develop organ-specific or cell-type-specific therapeutics.
“So far, scientists have looked at the relationship between HTRA1 and disease in binary terms,” notes Dichgans. “Our results show the importance of considering the activity of HTRA1 as a continuous phenotype.” In the future, the researchers intend to find out how the gene variants affect different cell types and tissues.
Original publication
Rainer Malik, Nathalie Beaufort, Jiang Li, Koki Tanaka, Marios K. Georgakis, Yunye He, Masaru Koido, Chikashi Terao, BioBank Japan, Christopher D. Anderson, Yoichiro Kamatani, Ramin Zand, Martin Dichgans; "Genetically proxied HTRA1 protease activity and circulating levels independently predict risk of ischemic stroke and coronary artery disease"; Nature Cardiovascular Research, 2024-5-20
Original publication
Rainer Malik, Nathalie Beaufort, Jiang Li, Koki Tanaka, Marios K. Georgakis, Yunye He, Masaru Koido, Chikashi Terao, BioBank Japan, Christopher D. Anderson, Yoichiro Kamatani, Ramin Zand, Martin Dichgans; "Genetically proxied HTRA1 protease activity and circulating levels independently predict risk of ischemic stroke and coronary artery disease"; Nature Cardiovascular Research, 2024-5-20
Topics
Organizations
Other news from the department science

Get the life science industry in your inbox
By submitting this form you agree that LUMITOS AG will send you the newsletter(s) selected above by email. Your data will not be passed on to third parties. Your data will be stored and processed in accordance with our data protection regulations. LUMITOS may contact you by email for the purpose of advertising or market and opinion surveys. You can revoke your consent at any time without giving reasons to LUMITOS AG, Ernst-Augustin-Str. 2, 12489 Berlin, Germany or by e-mail at revoke@lumitos.com with effect for the future. In addition, each email contains a link to unsubscribe from the corresponding newsletter.
More news from our other portals
Last viewed contents
Bone degradation process within metastatic breast cancer identified
New technique multiplies life span in simple organisms

Final report analytica 2012: Decision-makers announce definite intentions to invest - Live Labs generate a great deal of interest
Category:Medical_Council_of_India
Juvenile_idiopathic_arthritis
Woolly_hair_syndrome
Nomad Bioscience: new plant biotechnology company founded to focus on biomaterials and biopharmaceuticals
Usher_syndrome
Jawaharlal_Institute_of_Postgraduate_Medical_Education_&_Research
Phenytoin
Waardenburg_syndrome
