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 somatic 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. It most commonly arises due to loss-of-function mutations in regulators of DNA methylation. CHIP carriers 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, ablation of these genes in hematopoietic cells increases atherosclerosis in mouse models due to heightened transcription of inflammatory genes in the mutated innate 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. Here, we will use human cohorts with genetic sequencing data from 100,000s of people to identify novel disease associations of CHIP. We will use innovative approaches to interrogate sequence data from these datasets to identify factors that correlate with the rate of growth of mutant clones. 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. Finally, we will use tissue samples from humans with CHIP to understand the effect of these mutations on immune cell function and to address questions about tissue macrophage ontogeny in humans for the first time. These studies will broadly advance our knowledge about the causes and consequences of this common, newly described condition of aging.
Clonal hematopoiesis of indeterminate potential (CHIP) is a newly described entity that may have broad implications for human health. It results from somatic mutations in blood stem cells commonly acquired during aging, and is associated with increased risk of blood cancers, atherosclerotic cardiovascular disease, and death. Here, we will use large human genetic datasets combined with studies of human and mouse tissues to gain insight into the consequences and causes of CHIP.