TET2-mutant clonal hematopoiesis and risk of gout

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Fältnamn	Indikatorer	Metadata
000		05078naa a2200553 4500
001		oai:lup.lub.lu.se:27b44239-97c7-44cd-afda-cb505def24a4
003		SwePub
008		221129s2022 \| \|\|\|\|\|\|\|\|\|\|\|000 \|\|eng\|
024	7	a https://lup.lub.lu.se/record/27b44239-97c7-44cd-afda-cb505def24a42 URI
024	7	a https://doi.org/10.1182/blood.20220153842 DOI
040		a (SwePub)lu
041		a engb eng
042		9 SwePub
072	7	a art2 swepub-publicationtype
072	7	a ref2 swepub-contenttype
100	1	a Agrawal, Mridulu Dana-Farber Cancer Institute4 aut
245	1 0	a TET2-mutant clonal hematopoiesis and risk of gout
264	1	b American Society of Hematology,c 2022
300		a 10 s.
520		a 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.
650	7	a MEDICIN OCH HÄLSOVETENSKAPx Klinisk medicinx Reumatologi och inflammation0 (SwePub)302102 hsv//swe
650	7	a MEDICAL AND HEALTH SCIENCESx Clinical Medicinex Rheumatology and Autoimmunity0 (SwePub)302102 hsv//eng
700	1	a Niroula, Abhisheku Lund University,Lunds universitet,Hematogenomics,Forskargrupper vid Lunds universitet,LUCC: Lunds universitets cancercentrum,Övriga starka forskningsmiljöer,Lund University Research Groups,LUCC: Lund University Cancer Centre,Other Strong Research Environments,Dana-Farber Cancer Institute4 aut0 (Swepub:lu)med-anu
700	1	a Cunin, Pierreu Boston Children's Hospital4 aut
700	1	a McConkey, Marieu Dana-Farber Cancer Institute4 aut
700	1	a Shkolnik, Veronicau Dana-Farber Cancer Institute4 aut
700	1	a Kim, Peter G.u Broad Institute,Dana-Farber Cancer Institute4 aut
700	1	a Wong, Waihay J.u Dana-Farber Cancer Institute,Broad Institute4 aut
700	1	a Weeks, Lachelle D.u Dana-Farber Cancer Institute4 aut
700	1	a Lin, Amy E.u Dana-Farber Cancer Institute,Brigham and Women's Hospital / Harvard Medical School4 aut
700	1	a Miller, Peter G.u Harvard Medical School,Dana-Farber Cancer Institute4 aut
700	1	a Gibson, Christopher J.u Dana-Farber Cancer Institute4 aut
700	1	a Sekar, Aswinu Dana-Farber Cancer Institute4 aut
700	1	a Schaefer, Inga Marieu Harvard Medical School4 aut
700	1	a Neuberg, Donnau Dana-Farber Cancer Institute4 aut
700	1	a Stone, Richard M.u Dana-Farber Cancer Institute4 aut
700	1	a Bick, Alexander G.u Vanderbilt University Medical Center4 aut
700	1	a Uddin, Md Mesbahu Broad Institute,Massachusetts General Hospital4 aut
700	1	a Griffin, Gabriel K.u Broad Institute,Harvard Medical School4 aut
700	1	a Jaiswal, Siddharthau Stanford University School of Medicine4 aut
700	1	a Natarajan, Pradeepu Massachusetts General Hospital,Harvard Medical School,Broad Institute4 aut
700	1	a Nigrovic, Peter A.u Harvard Medical School,Boston Children's Hospital4 aut
700	1	a Rao, Deepak A.u Harvard Medical School4 aut
700	1	a Ebert, Benjamin L.u Dana-Farber Cancer Institute,Howard Hughes Medical Institute4 aut
710	2	a Dana-Farber Cancer Instituteb Hematogenomics4 org
773	0	t Bloodd : American Society of Hematologyg 140:10, s. 1094-1103q 140:10<1094-1103x 0006-4971x 1528-0020
856	4	u http://dx.doi.org/10.1182/blood.2022015384x freey FULLTEXT
856	4 8	u https://lup.lub.lu.se/record/27b44239-97c7-44cd-afda-cb505def24a4
856	4 8	u https://doi.org/10.1182/blood.2022015384

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