Clonal hematopoiesis and risk of chronic liver disease

Chronic liver disease is a major public health burden worldwide. Despite various liver injury mechanisms, progression of chronic liver disease follows a common pathway of liver inflammation, injury and fibrosis. We examined the association between clonal hematopoiesis of indeterminate potential (CHIP) and chronic liver disease in 58,358 individuals from four prospective cohorts with whole exome sequencing data (Framingham Heart Study, Atherosclerosis Risk in Communities Study, UK Biobank and Mass General Brigham Biobank). CHIP was associated with an increased risk of prevalent chronic liver disease (OR 2.70 CI 1.42, 5.16, p=0.002) and incident chronic liver disease (HR 2.01 CI 1.46, 2.79, p=0.001) from both alcoholic and nonalcoholic causes. Individuals with CHIP showed 75% greater odds of MRI detectable liver inflammation and fibrosis (5.9% versus 3.5%, p=0.007) compared to those without CHIP. To assess causality, Mendelian randomization analyses showed that genetic predisposition to CHIP was associated with a greater risk of chronic liver disease (OR 2.37 CI 1.57, 3.6, p<0.001). In a dietary model of nonalcoholic steatohepatitis (NASH), mice transplanted with Tet2-deficient hematopoietic cells demonstrated more severe liver inflammation and fibrosis. These effects were mediated via NLRP3 inflammasome and increased downstream inflammatory cytokine expression, including IL6. In summary, clonal hematopoiesis is associated with an elevated risk of liver inflammation and chronic liver disease progression via an aberrant inflammatory response.