TET2-mutant clonal hematopoiesis and risk of gout

• Published in: Blood Vol. 140; no. 10; pp. 1094 - 1103
• Main Authors: Agrawal, Mridul, Niroula, Abhishek, Cunin, Pierre, McConkey, Marie, Shkolnik, Veronica, Kim, Peter G., Wong, Waihay J., Weeks, Lachelle D., Lin, Amy E., Miller, Peter G., Gibson, Christopher J., Sekar, Aswin, Schaefer, Inga-Marie, Neuberg, Donna, Stone, Richard M., Bick, Alexander G., Uddin, Md Mesbah, Griffin, Gabriel K., Jaiswal, Siddhartha, Natarajan, Pradeep, Nigrovic, Peter A., Rao, Deepak A., Ebert, Benjamin L.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 08.09.2022; American Society of Hematology
• Subjects: Animals; Clinical Medicine; Clonal Hematopoiesis; Dioxygenases - genetics; DNA-Binding Proteins - genetics; Gout - genetics; Hematopoiesis and Stem Cells; Humans; Inflammasomes - genetics; Interleukin-1beta - genetics; Klinisk medicin; Medical and Health Sciences; Medicin och hälsovetenskap; Mice; NLR Family, Pyrin Domain-Containing 3 Protein - genetics; Reumatologi och inflammation; Rheumatology and Autoimmunity; Uric Acid - chemistry; Uric Acid - pharmacology
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood.2022015384

Gout is a common inflammatory arthritis caused by precipitation of monosodium urate (MSU) crystals in individuals with hyperuricemia. Acute flares are accompanied by secretion of proinflammatory cytokines, including interleukin-1β (IL-1β). Clonal hematopoiesis of indeterminate potential (CHIP) is an age-related condition predisposing to hematologic cancers and cardiovascular disease. CHIP is associated with elevated IL-1β, thus we investigated CHIP as a risk factor for gout. To test the clinical association between CHIP and gout, we analyzed whole exome sequencing data from 177 824 individuals in the MGB Biobank (MGBB) and UK Biobank (UKB). In both cohorts, the frequency of gout was higher among individuals with CHIP than without CHIP (MGBB, CHIP with variant allele fraction [VAF] ≥2%: odds ratio [OR], 1.69; 95% CI, 1.09-2.61; P = .0189; UKB, CHIP with VAF ≥10%: OR, 1.25; 95% CI, 1.05-1.50; P = .0133). Moreover, individuals with CHIP and a VAF ≥10% had an increased risk of incident gout (UKB: hazard ratio [HR], 1.28; 95% CI, 1.06-1.55; P = .0107). In murine models of gout pathogenesis, animals with Tet2 knockout hematopoietic cells had exaggerated IL-1β secretion and paw edema upon administration of MSU crystals. Tet2 knockout macrophages elaborated higher levels of IL-1β in response to MSU crystals in vitro, which was ameliorated through genetic and pharmacologic Nlrp3 inflammasome inhibition. These studies show that TET2-mutant CHIP is associated with an increased risk of gout in humans and that MSU crystals lead to elevated IL-1β levels in Tet2 knockout murine models. We identify CHIP as an amplifier of NLRP3-dependent inflammatory responses to MSU crystals in patients with gout. •TET2-mutant clonal hematopoiesis is associated with increased risk of incident gout.•Monosodium urate crystal treatment exacerbates Nlrp3-dependent IL-1β secretion and functional impairment in transplanted Tet2-knockout mice. [Display omitted]