The accumulation of somatic DNA mutations over time is a hallmark of aging in many tissues. However, the causal role of somatic mutations in age-associated disorders other than cancer is a matter of debate, and remains unexplored in the setting of cardiovascular disease (CVD), the leading cause of death in elderly individuals. Recent large exome sequencing studies in humans have shown that aging is inevitably associated with an increased frequency of somatic mutations in the hematopoietic system, which provide a competitive growth advantage to the mutant cell and thus allow its clonal expansion (clonal hematopoiesis). Unexpectedly, these somatic mutations were associated with a higher rate of cardiovascular-related deaths, suggesting a previously unrecognized link between somatic mutations in bone marrow-derived cells and CVD . However, whether there is a causal connection between these somatic mutations and CVD remains unclear and the potential underlying mechanisms are completely unknown, and this is the scientific premise of the proposed research.
The accumulation of somatic DNA mutations over time is a hallmark of aging in many tissues. However, the causal role of somatic mutations in age-associated disorders other than cancer is a matter of debate, and remains unexplored in the setting of cardiovascular disease, the leading cause of death in elderly individuals. The proposed research seeks to determine if there is a causal connection between relatively common somatic mutations in the hematopoietic system and cardiovascular disease, and to ascertain the potential underlying mechanisms.
| Sano, Soichi; Oshima, Kosei; Wang, Ying et al. (2018) Tet2-Mediated Clonal Hematopoiesis Accelerates Heart Failure Through a Mechanism Involving the IL-1?/NLRP3 Inflammasome. J Am Coll Cardiol 71:875-886 |
| Sano, Soichi; Wang, Ying; Walsh, Kenneth (2018) Clonal Hematopoiesis and Its Impact on Cardiovascular Disease. Circ J 83:2-11 |
| Fuster, José J; Walsh, Kenneth (2018) Somatic Mutations and Clonal Hematopoiesis: Unexpected Potential New Drivers of Age-Related Cardiovascular Disease. Circ Res 122:523-532 |
| Sano, Soichi; Oshima, Kosei; Wang, Ying et al. (2018) CRISPR-Mediated Gene Editing to Assess the Roles of Tet2 and Dnmt3a in Clonal Hematopoiesis and Cardiovascular Disease. Circ Res 123:335-341 |
