Approved Research

Clonal hematopoiesis of indeterminate potential (CHIP) in aging and disease

Lay summary

Diseases of aging such as heart disease and stroke are usually thought to occur due to a combination of hereditary and environmental influences. Recently, we discovered that somatic mutations (DNA alterations acquired after birth) in blood cells may be another factor that contributes to these diseases. Approximately 15-20% of people age 70 or older carry a cancer-associated mutation in a substantial proportion of their blood cells, even though the vast majority do not have cancer. This condition has been termed "clonal hematopoiesis of indeterminate potential", or CHIP. Carriers of CHIP develop blood cancers at a higher rate than the general population, which is expected because it represents the "first-hit" on the path to cancer. Surprisingly, CHIP is also associated with increased all-cause mortality and higher risk of developing non-neoplastic diseases, like atherosclerotic cardiovascular disease. Mechanistically, CHIP mutations increase atherosclerosis due to heightened transcription of inflammatory genes in immune cells. CHIP is the first example of somatic variation acting as a causal factor for common diseases of aging apart from cancer, but a detailed understanding of its consequences for human health is lacking.  Because of its link to immune function, inflammation, and aging, we hypothesize that CHIP will also influence many other diseases of aging.

Over the next two years, we will use data from UKB to identify novel disease associations of CHIP. We will use novel approaches to interrogate sequence data from these datasets to identify factors that correlate with the rate of growth of mutant cells. We will also leverage the information collected in these biobanks to improve our ability to predict who will suffer adverse consequences, which is a major barrier to developing clinical interventions for CHIP. These studies will broadly advance our knowledge about the causes and consequences of this common, newly described condition of aging.