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Clonal Hematopoiesis of Indeterminate Potential Linked to Increased Risk of Chronic Liver Disease

NEW YORK — Researchers at Harvard University and elsewhere have found that clonal hematopoiesis of indeterminate potential (CHIP) not only confers a twofold increased risk of developing chronic liver disease but could also play a causal role in liver disease development.

Previous studies have linked CHIP with cancer and atherosclerotic cardiovascular disease.

"Our findings support a model of CHIP promoting steatohepatitis particularly among individuals with elevated liver fat or other sources of liver injury that increase cirrhosis risk," corresponding author Pradeep Natarajan, associate professor of medicine at Harvard Medical School, and colleagues wrote in their paper, which was published in Nature on Wednesday.

In this study, the researchers examined the association between CHIP and chronic liver disease in 214,563 individuals from four independent cohorts — the Framingham Heart Study (FHS), the Atherosclerosis Risk in Communities Study (ARIC), the UK Biobank, and the Mass General Brigham Biobank. They used their whole-exome sequencing data to look for mutations in genes that are known to affect CHIP development.

A meta-analysis of a cross-sectional cohort of individuals from the UK Biobank, ARIC, and FHS showed a significant effect of CHIP on risk of nonalcoholic steatohepatitis (NASH), a common cause of chronic liver disease. Further, abdominal MRI data from 8,251 individuals from the UK Biobank indicated that people with CHIP were more likely to have liver inflammation and fibrosis.

To corroborate their findings on CHIP and NASH, the researchers also carried out phenome-wide Mendelian randomization analyses across 22 phenotypes, including risk factors for cardiac conditions, autoimmune diseases, and solid malignancies. The findings confirmed that the association between CHIP and chronic liver disease was indeed specific.

"We observed that germline genetic predisposition to CHIP predisposes to chronic liver disease risk. Therefore, CHIP is probably a causal risk factor for chronic liver disease," the authors wrote.

A murine model of hematopoietic-specific Tet2 inactivation, a mutation commonly seen in CHIP, showed a higher severity of diet-induced steatohepatitis. These mice had more lobular inflammation with prominent lymphoid aggregates and hepatocyte ballooning, without apparent influence on liver fat, compared to the controls, showing the impact of CHIP on the tissues, histological studies showed.

"These findings demonstrate that Tet2-deficient hematopoietic cells promote the development of steatohepatitis in mice," the authors wrote.

The presence of CHIP in these mice also led to an increase in proinflammatory effects of macrophages through downstream cytokine secretion, which is known to promote steatohepatitis and fibrosis, serum analysis showed. The authors said that this process of increase in proinflammatory effects requires the upstream regulator NLRP3.

"Considering the heterogeneous nature of the cell types involved, broad pharmacologic inhibition of the NLRP3 inflammasome is one potential strategy for modifying liver inflammation and fibrosis in CHIP," the authors said. However, further in vivo and preclinical testing will be required to determine safety, they added.