So a variety of impactful original studies have noted the distinct association between CHIP and incident organ dysfunction. CHIP is relevant to a lot of different fields within internal medicine, including cardiology, nephrology, hepatology, pulmonary medicine, rheumatology, and even endocrinology. The most notable link is with the field of cardiology. Back in 2017, the Ebert lab actually characterized this association by performing whole exome sequencing to detect CHIP in the peripheral blood, and they associated this with coronary artery disease...
So a variety of impactful original studies have noted the distinct association between CHIP and incident organ dysfunction. CHIP is relevant to a lot of different fields within internal medicine, including cardiology, nephrology, hepatology, pulmonary medicine, rheumatology, and even endocrinology. The most notable link is with the field of cardiology. Back in 2017, the Ebert lab actually characterized this association by performing whole exome sequencing to detect CHIP in the peripheral blood, and they associated this with coronary artery disease. They had a case control study, which enrolled about 4,700 participants and 3,500 controls, and they found that CHIP was linked with increased risk of coronary artery disease, and that risk was about 1.9 times greater compared to non-carriers of CHIP. And they found that the mutations that were linked with coronary artery disease were DNMT3A, TET2, ASXL1, and JAK2. CHIP carriers with these mutations had increased coronary artery calcifications and markers of coronary atherosclerosis. To assess causality, they used a VAV1 Cre system to induce the knockout of TET2 just in hematopoietic cells. The VAV1 promoter is a DNA regulatory element that drives expression primarily within the hematopoietic system, so they were able to knock out TET2 within the hematologic compartment. When they disrupted the function of TET2, they found increased atherosclerosis within murine models.
CHIP is also linked with pulmonology. In pulmonary medicine, there was a study showing the link between CHIP and chronic obstructive pulmonary disease. The team at the Brigham and Women’s Hospital analyzed whole exome sequencing to detect CHIP in about 48,000 people from the COPD gene cohort, as well as other cohorts. The COPD gene cohort is one of the largest annotated cohorts for chronic obstructive pulmonary disease. And they found that in TET2 knockout murine hematopoietic stem cells, in mice that had TET2 knockout HSCs, there was increased emphysema and inflammation in models of cigarette smoke exposure.
It’s also linked with hepatology. So CHIP has relevance to hepatology based on a very nice study by Dr. Natarajan’s group from MGH Cardiology in Nature in 2023, where they analyzed whole exome sequencing data from about 214,000 people from multiple independent cohorts, including the Framingham Heart Study, the UK Biobank, and the Mass General Program Biobank. And they reported that CHIP was associated with an increased risk for incident chronic liver disease. And it was thought that there was increased liver inflammation and fibrosis in the setting of having CHIP.
CHIP is also linked with nephrology. Alexander Bix’s group from Vanderbilt showed the negative impact of CHIP in acute kidney injury. And they analyzed three large population-based registries, including the UK Biobank, the National Heart, Lung, Blood Institute, atherosclerosis Risk and Community Study, as well as the Cardiovascular Heart Study. And they found that CHIP was associated with an increased risk for incident acute kidney injury. And specifically, this was for TET2- and JAK2-mutant CHIP.
CHIP is also linked to rheumatology. Dr. Ben Ebert’s group analyzed whole exome sequencing from about 177,000 people from the Mass General Brigham Biobank as well as the UK Biobank. And in both cohorts, they found that CHIP was linked with increased risk for having gout. And they analyzed this in murine models of gout pathogenesis using TET2 knockout hematopoietic stem cells and found increased IL-1 beta secretion and paw edema upon administration of monosodium urate in these gout models.
And finally, in endocrinology, there’s a link between CHIP and osteoporosis. The team had analyzed whole exome sequencing data from the UK Biobank, and they found that DNMT3A mutant CHIP specifically was associated with increased incident osteoporosis and increased osteoclast activity.
So in summary, CHIP is a multi-system disease. It’s known that subclinical clonal hematopoietic expansion can cause or can contribute to multiple health conditions. And these studies have informed our own team’s work. We aim to characterize CHIP in the background of having had treatment for other conditions, specifically after chemotherapy for solid tumors, for rheumatologic conditions, and for autoimmune conditions. And in the field of medical oncology, we’ve seen remarkable progress in terms of survival outcomes for solid tumors. But the one downside of better survivorship is that there’s also increased lead time for the eventual development of a therapy-related myeloid neoplasm. If a patient lives long enough after having exposure to chemotherapy, the hematopoietic stem cells can become disrupted, and at some point, they can eventually develop a therapy-related myeloid neoplasm. So our goal was to characterize therapy-related CHIP from our multidisciplinary CHIP clinic at UMass in order to understand the real-world relevance and the origins and evolution of therapy-related CHIP.
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