Proteins circulating in the blood can reveal what’s happening in the body, from how we process energy to how diseases develop. Unlike genetic testing, which shows fixed risk factors from birth, protein analysis provides a real-time picture of health and disease. 

Research published in Circulation: Genomic and Precision Medicine and led by Dr Kathryn McGurk from the Computational Cardiac Imaging group and the Cardiovascular Genomics Precision Medicine group at the LMS has shed light on how certain proteins in our blood connect cardiovascular risk factors with disease development and outcomes. 

“To fully predict, stratify and prevent people from getting heart disease, we need new biomarkers and targets for treatment,” says Kathryn, “so our goal was to understand whether studying the proteins already linked to heart disease through genetics could illustrate risk more clearly and determine whether they could be used in clinical blood tests.” 

To do this, the team analysed nine key proteins in over 45,000 blood samples from the UK Biobank. These included ACE2, BNP, NT-proBNP, and troponin I — proteins known to play roles in heart function and disease. They found significant variability in circulating proteins depending on age, sex, ancestry, genetics, lifestyle and medication use.  

The ACE2 protein: Counteracting high blood pressure 

ACE2 levels were increased in individuals with a diagnosis of high blood pressure or diabetes, both of which are risk factors for heart disease. The effect was seen particularly in females and was influenced by changes in genes that are associated with diabetes. Using a genetic analysis method called two‑sample Mendelian randomisation, the researchers found evidence that these higher ACE2 levels may, in fact, be trying to protect against high blood pressure and type-2 diabetes. 

ACE2 drew global attention during the COVID-19 pandemic as it’s the protein that allows the virus to enter human cells. ACE2 breaks down angiotensin II, a compound that tightens blood vessels, and produces substances that relax blood vessels. In this way, the elevated levels of ACE2 seen in individuals with high blood pressure may be compensatory, by helping to relax constricted blood vessels. 

Since high blood pressure and diabetes are so widespread, identifying ACE2 as a new and relatively unexplored biomarker could have important implications for patient care. ACE2 appears to have protective effects in the cardiovascular system, through its role in helping to relax blood vessels and counteracting the activity of hormones that raise blood pressure.  

What could this mean for blood pressure and diabetes treatments? 

ACE inhibitors are common drugs for treating high blood pressure and work by blocking the ACE1 protein which, in contrast to ACE2, makes angiotensin II. These findings could influence how ACE inhibitor drugs are used and by which patients, as it’s likely that ACE2:ACE1 balance has a role in how successful ACE inhibitors are in treating blood pressure. Individuals with naturally altered levels of ACE2 may be better suited to certain ACE inhibitors, and this may lead to more tailored treatments based on blood ACE2 levels.

Future research will explore whether increasing ACE2 activity or mimicking its effects could improve treatment for high blood pressure and diabetes. Previous preclinical studies of a common anti-diabetic drug, metformin, showed that it increases ACE2 expression as part of its action. 

“This work highlights how discovery data science can find novel disease biomarkers and therapies, as well as shift our understanding of current therapies and which patients can benefit most,” says Kathryn.  “The key to this work is interdisciplinary collaboration: with our enthusiastic early career colleagues (Dr Lara Curran, Dr Arun Sau), encouragement and input from more senior colleagues (Prof Declan O’Regan, Prof James Ware, Prof Fu Siong Ng), and important clinical insights (Dr Brian Halliday).” 

This research was primarily supported by British Heart Foundation, the Medical Research Council, the National Institute for Health and Care Research (NIHR) Imperial College Biomedical Research Center, the Sir Jules Thorn Charitable Trust and Rosetrees Trust.  

Kathryn is a British Heart Foundation Immediate Research Fellow at the LMS and Imperial’s National Heart and Lung Institute. 

Read the full publication: https://www.ahajournals.org/doi/10.1161/CIRCGEN.124.005005