Through advances in population-based genomic sequencing an analysis, the Natarajan lab and others showed that ‘clonal hematopoiesis of indeterminate potential’ (CHIP) is a surprisingly common feature as we age. They also showed that CHIP plays a role in coronary artery disease, the leading contributor to death in the US and now globally. As inflammation appeared to be a principal driver, the Natarajan lab has since then attempted to understand whether CHIP plays a role in other conditions where inflammation has been invoked as a key driver. This study focused on chronic liver disease because, which has become increasingly common with the rising prevalence of obesity and metabolic syndrome. However, therapeutic options for chronic liver disease have remained limited for decades except for hepatitis C. Fatty liver disease is increasingly recognized but the reasons by inflammation and downstream liver disease occur remain limited. They therefore hypothesized that CHIP could play a role. It was found that CHIP offered to confer a relatively large risk for chronic liver disease, sometimes larger than currently recognized risk factors. And causal inference approaches, such as Mendelian randomization, supported a potential causal relationship. Liver MRIs and liver biopsies were consistent with greater steatohepatitis and not greater steatosis. Murine models similarly showed greater steatohepatitis without greater steatosis, and also greater fibrosis when followed for longer periods of time. Genetic deficiency of the NLRP3 inflammasome appeared to ameliorate this phenotype in the mice. This inflammatory pathway has also been invoked in CHIP-associated coronary artery disease. The relationship between CHIP and liver disease was previously unknown. These observations highlight a new potential precision medicine paradigm for chronic liver disease prevention. The findings support the scientific premise that, particularly for TET2 CHIP, inhibition of the NLRP3 inflammasome may reduce the risk of chronic liver disease.

Read more in Nature.