The HEARTLY project focuses on a lasting conundrum in medicine: the fact that men in the entire world live on average 5-6 years shorter lives compared with women. In the project we study the effects from mosaic loss of chromosome Y (mLOY), a male specific somatic mutation that helps explain this bias. Men with mLOY in blood carry a fraction of blood cells without the Y chromosome, due to its loss from hematopoietic progenitor cells during life time. The incidence of mLOY increases with age and is the most common somatic human mutation. The mutation can be detected in at least 5% of peripheral blood cells in about 5%, 20%, 40% and 60% of normally aging men around 50, 60, 70 and 90 years of age. Based on incidence observed in studied cohorts and global demographics data, more than 200 million men might be affected with mLOY in blood. Known risk factors include aging, smoking, genetic predisposition and exposure to various pollutants.
At the onset of the project, it was already established that men with mLOY display an increased risk for all-cause mortality, in part explained by increased risk for several common diseases such as cancer and Alzheimer’s disease. However, it was not known if men with mLOY in blood had an increased risk for the biggest killer of all, i.e. the cardiovascular diseases (CVD). One of the objectives in the HEARTLY project is to investigate risk for CVD in relation to mLOY. During the first period of the project, we have established that men with mLOY in blood indeed have an increased risk for death in CVD overall and interestingly, that mLOY is specifically associated with risk for death in hypertensive heart disease, aortic aneurysm and heart failure. In the continuation of the project we aim to continue our investigations of these and other disease associations using analyses of outcomes in prospective cohorts.
Another objective of the project is to enhance our understanding of causal link(s) between mLOY in blood and disease in other organs. This is a major task and we approach it by several complimentary strategies. A major milestone of the project was the finding that mLOY is causally related with mortality. Furthermore, by studying altered gene expression in LOY-cells, we have discovered that leukocytes without the Y chromosome trigger profibrotic signalling pathways, leading to organ dysfunction and exacerbation of disease. Hence, fibrosis is a major component of many LOY-associated diseases and thus, it is hypothesized that enhanced fibrosis represents a unifying disease mechanism, explaining how mLOY in blood cells is associated with all major causes of death. A next step that is pursued in the project is the identification of specific genetic elements of the Y chromosome that could be responsible for the profound phenotypic effects associated with Y loss. We are using several methods for gene editing and transcriptional silencing in different model systems to achieve this goal.
A long-term goal of our research is an increased survival of men by utilization of mLOY-based clinical applications. Enhanced understanding of detrimental effects from mLOY on human physiology could be a key to improved success rates in various therapies, stratification and discovery of new drug targets. For example, since men with mLOY in blood have on average a higher risk for lethal disease compared with unaffected men, we envision that screening men with mLOY for early symptoms of disease could result in earlier diagnoses and treatment using existing health care options. In the project we are therefore working on developing clinically feasible tools for mLOY detection to improve such translational efforts. Our discovery of profibrotic signalling of LOY-leukocytes represents an important step in this direction, as approved antifibrotic treatments are already used clinically. Overall, the deliverables of the project has the potential to become beneficial for individual patients, health care systems and societies at large.
