The p53 gene in cells is an old acquaintance with researchers in the development of different types of cancer, including blood cancers, when there are mutations. What was not known, and a study carried out by Spanish researchers discovers, is that mutations in this same gene are also involved in the development of atherosclerotic cardiovascular disease.
Known as the Guardian of the Genome, the protein encoded by the p53 gene helps maintain the integrity of cells’ hereditary material, regulating multiple cellular functions in response to different forms of stress.
In a study published in “Nature Cardiovascular Research”, the group led by José Javier Fuster, a researcher at the National Center for Cardiovascular Research (CNIC), shows that these mutations also accelerate the development of atherosclerosis, the underlying cause of the greater part of cardiovascular diseases, the first cause of mortality in the world and one of the greatest economic burdens for health systems.
Every day, an adult person generates hundreds of billions of blood cells.. However, this necessary process facilitates the appearance of mutations in the cells responsible for their production.
In collaboration with other groups, the researchers analyzed blood cell data from more than 50,000 people.
“We found that carriers of acquired p53 mutations are at increased risk of developing coronary artery disease and peripheral artery disease, completely independent of the traditional cardiovascular risk factors, such as high blood pressure or high blood cholesterol levels», explains José Javier Fuster.
The results of their studies in animal models of atherosclerosis showed that mice carrying p53 mutations developed atherosclerosis in an accelerated manner, mainly due to an abnormally high proliferation of immune cells in the artery walls.
“This combination of human observations and experimental animal studies provides strong evidence that these mutations increase the risk of developing cardiovascular disease,” says Fuster.
For Valentin Fusterdirector general of the CNIC and one of the authors of the research, this work “expands knowledge of the role of mutations acquired in blood cells, a phenomenon called clonal hematopoiesis, as a new cardiovascular risk factor.”
José Javier Fuster believes that in the medium term, detecting acquired mutations in p53 or in other genes linked to hematopoyesis clonal could contribute to the identification of high-risk patients, both in terms of cardiovascular disease and haematological malignancies. And in the longer term, he adds, “identifying these mutations” will help you design personalized cardiovascular risk prevention strategies, aimed at preventing the specific effects of these mutations.”
However, this will still require years of research and new clinical trials, he acknowledges.
Identifying these mutations “will help you design personalized cardiovascular risk prevention strategies
Thus, regarding the possibility of detecting these mutations in daily clinical practice, Fuster affirms that although some of these mutations are already detected in clinical practice in the context of the characterization of haematological neoplasms, “the sequencing strategies and computer analysis that would be applicable to the population free of this type of cancer are still difficult to apply in daily clinical practice. In this sense, we are collaborating with computer scientists and experts in clinical genetics in order to develop sequencing panels and bioinformatics tools adapted to the clinical field”.
The researchers point out that the mechanisms by which mutations in different genes contribute to cardiovascular disease are different, “which may in the future open the door to personalized prevention strategies of cardiovascular disease targeting the specific effects of the various mutations,” says Nuria MatesanzCNIC researcher and co-first author of the article.
In the case of atherosclerotic cardiovascular disease, adds the researcher, the objective is to improve prevention, both in the context of primary prevention and in that of secondary prevention in patients who already have evidence of cardiovascular disease.
In the future, it will be possible to design personalized strategies for the prevention of cardiovascular disease directed at the specific effects of the different mutations.
The main limitation is the design of therapeutic interventions. Fuster explains, “for the majority of mutations linked to clonal hematopoiesis, including those that affect the p53 gene, we lack sufficient evidence to identify interventions that prevent or attenuate the cardiovascular risk associated with these mutations. In this sense, the article that we are now publishing suggests that Interventions that stop the proliferation of macrophages they could be effective in the case of mutations in p53, but new studies will be necessary to demonstrate this possibility”.
For other mutations, such as those that affect the TET2 gene, also studied in this article, it has previously been shown that drugs that inhibit the cytokine IL-1beta, such as canakinumab, can prevent the cardiovascular risk associated with these mutations. However, he acknowledges that this is based on experiments in animal models and retrospective analyzes of clinical trials with this drug, for which “new clinical trials will be necessary to evaluate this possibility prospectively.”