Loss of chromosome Y in immune cells: targeting disease mechanisms and tools for clinical applications

ongoing

Men live shorter and are more susceptible to several common diseases at younger ages compared with women, but the reason(s) why are not well understood. Loss of chromosome Y (LOY) is a male specific mutation that could help explain this sex bias. Men with LOY carry a fraction of blood cells without the Y chromosome, due to its loss from progenitor cells during life time. The incidence of LOY increases with age and can be detected in blood among 40% of 70 year old men. My recent results show that LOY in blood is strongly associated with increased risk for all-cause mortality and disease such as cancer and Alzheimer’s disease, and possibly cardiovascular disease. The causal link(s) behind reproducible associations between LOY in blood and disease are yet to be discovered. My proposal aims for comprehensive understanding of the cellular changes induced by LOY in immune cells and delineation of associated disease mechanisms that could explain why men with LOY in the immune cells of blood have a higher risk for disease in other organs. To this end, several complementary studies are conceived in three synergistic objectives: 1) functional consequences of LOY in immune cells; 2) epidemiological studies of 570.000 subjects with focus on LOY and risk for cardiovascular disease; and 3) development of new tools for LOY-detection. My long-term goal is increased survival of men by utilization of LOY-based clinical applications. For example, men with LOY in blood have on average a higher risk for lethal disease compared with unaffected men. Hence, screening men with LOY for early symptoms of disease could result in earlier diagnoses and treatment using existing health care options. Furthermore, understanding of detrimental effects from LOY on immune system functions could be a key to improved success rates in immunotherapy as well as for identification of new drug targets. Taken together, the project will benefit patients, health care systems and societies at large.