Clonal haematopoiesis and risk of chronic liver disease
Journal
Nature
Journal Volume
616
Journal Issue
7958
Pages
747 - 754
Date Issued
2023-04
Author(s)
Wong, Waihay J
Emdin, Connor
Bick, Alexander G
Zekavat, Seyedeh M
Niroula, Abhishek
Pirruccello, James P
Dichtel, Laura
Griffin, Gabriel
Uddin, Md Mesbah
Gibson, Christopher J
Kovalcik, Veronica
Lin, Amy E
McConkey, Marie E
Vromman, Amelie
Sellar, Rob S
Kim, Peter G
Agrawal, Mridul
Weinstock, Joshua
Long, Michelle T
Yu, Bing
Banerjee, Rajarshi
Nicholls, Rowan C
Dennis, Andrea
Kelly, Matt
Loh, Po-Ru
McCarroll, Steve
Boerwinkle, Eric
Vasan, Ramachandran S
Jaiswal, Siddhartha
Johnson, Andrew D
Chung, Raymond T
Corey, Kathleen
Levy, Daniel
Ballantyne, Christie
Ebert, Benjamin L
Natarajan, Pradeep
Abstract
Chronic liver disease is a major public health burden worldwide1. Although different aetiologies and mechanisms of liver injury exist, progression of chronic liver disease follows a common pathway of liver inflammation, injury and fibrosis2. Here we examined the association between clonal haematopoiesis of indeterminate potential (CHIP) and chronic liver disease in 214,563 individuals from 4 independent 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 and incident chronic liver disease (odds ratio = 2.01, 95% confidence interval (95% CI) [1.46, 2.79]; P < 0.001). Individuals with CHIP were more likely to demonstrate liver inflammation and fibrosis detectable by magnetic resonance imaging compared to those without CHIP (odds ratio = 1.74, 95% CI [1.16, 2.60]; P = 0.007). To assess potential causality, Mendelian randomization analyses showed that genetic predisposition to CHIP was associated with a greater risk of chronic liver disease (odds ratio = 2.37, 95% CI [1.57, 3.6]; P < 0.001). In a dietary model of non-alcoholic steatohepatitis, mice transplanted with Tet2-deficient haematopoietic cells demonstrated more severe liver inflammation and fibrosis. These effects were mediated by the NLRP3 inflammasome and increased levels of expression of downstream inflammatory cytokines in Tet2-deficient macrophages. In summary, clonal haematopoiesis is associated with an elevated risk of liver inflammation and chronic liver disease progression through an aberrant inflammatory response.
SDGs
Type
journal article