{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,27]],"date-time":"2026-10-27T01:39:50Z","timestamp":1793065190560,"version":"4.5.0"},"reference-count":34,"publisher":"American Society of Hematology","issue":"10","license":[{"start":{"date-parts":[[2022,6,17]],"date-time":"2022-06-17T00:00:00Z","timestamp":1655424000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/legalcode"}],"content-domain":{"domain":["ashpublications.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2022,9,8]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>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-1\u03b2 (IL-1\u03b2). Clonal hematopoiesis of indeterminate potential (CHIP) is an age-related condition predisposing to hematologic cancers and cardiovascular disease. CHIP is associated with elevated IL-1\u03b2, 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\u2009824 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] \u22652%: odds ratio [OR], 1.69; 95% CI, 1.09-2.61; P = .0189; UKB, CHIP with VAF \u226510%: OR, 1.25; 95% CI, 1.05-1.50; P = .0133). Moreover, individuals with CHIP and a VAF \u226510% 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-1\u03b2 secretion and paw edema upon administration of MSU crystals. Tet2 knockout macrophages elaborated higher levels of IL-1\u03b2 in response to MSU crystals in\u00a0vitro, 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-1\u03b2 levels in Tet2 knockout murine models. We identify CHIP as an amplifier of NLRP3-dependent inflammatory responses to MSU crystals in patients with gout.<\/jats:p>","DOI":"10.1182\/blood.2022015384","type":"journal-article","created":{"date-parts":[[2022,6,17]],"date-time":"2022-06-17T15:53:39Z","timestamp":1655481219000},"page":"1094-1103","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":172,"title":["<i>TET2<\/i>\n                    -mutant clonal hematopoiesis and risk of gout"],"prefix":"10.1182","volume":"140","author":[{"given":"Mridul","family":"Agrawal","sequence":"first","affiliation":[{"name":"1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abhishek","family":"Niroula","sequence":"additional","affiliation":[{"name":"1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA;"},{"name":"2Broad Institute of Harvard and MIT, Cambridge, MA;"},{"name":"3Department of Laboratory Medicine, Lund University, Lund, Sweden;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8550-2306","authenticated-orcid":false,"given":"Pierre","family":"Cunin","sequence":"additional","affiliation":[{"name":"4Division of Immunology, Boston Children's Hospital, Boston, MA;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marie","family":"McConkey","sequence":"additional","affiliation":[{"name":"1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Veronica","family":"Shkolnik","sequence":"additional","affiliation":[{"name":"1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter G.","family":"Kim","sequence":"additional","affiliation":[{"name":"1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA;"},{"name":"2Broad Institute of Harvard and MIT, Cambridge, MA;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2023-6590","authenticated-orcid":false,"given":"Waihay J.","family":"Wong","sequence":"additional","affiliation":[{"name":"1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA;"},{"name":"2Broad Institute of Harvard and MIT, Cambridge, MA;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8726-6212","authenticated-orcid":false,"given":"Lachelle D.","family":"Weeks","sequence":"additional","affiliation":[{"name":"1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0554-2832","authenticated-orcid":false,"given":"Amy E.","family":"Lin","sequence":"additional","affiliation":[{"name":"1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA;"},{"name":"2Broad Institute of Harvard and MIT, Cambridge, MA;"},{"name":"3Department of Laboratory Medicine, Lund University, Lund, Sweden;"},{"name":"4Division of Immunology, Boston Children's Hospital, Boston, MA;"},{"name":"5Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, MA;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6797-9335","authenticated-orcid":false,"given":"Peter G.","family":"Miller","sequence":"additional","affiliation":[{"name":"1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA;"},{"name":"6Division of Hematology, Department of Medicine, Brigham and Women\u2019s Hospital, Harvard Medical School, Boston, MA;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher J.","family":"Gibson","sequence":"additional","affiliation":[{"name":"1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aswin","family":"Sekar","sequence":"additional","affiliation":[{"name":"1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9710-5500","authenticated-orcid":false,"given":"Inga-Marie","family":"Schaefer","sequence":"additional","affiliation":[{"name":"7Department of Pathology, Brigham and Women\u2019s Hospital, Harvard Medical School, Boston, MA;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Donna","family":"Neuberg","sequence":"additional","affiliation":[{"name":"8Department of Data Science, Dana-Farber Cancer Institute, Boston, MA;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard M.","family":"Stone","sequence":"additional","affiliation":[{"name":"1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander G.","family":"Bick","sequence":"additional","affiliation":[{"name":"9Division of Genetic Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1846-0411","authenticated-orcid":false,"given":"Md Mesbah","family":"Uddin","sequence":"additional","affiliation":[{"name":"10Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA;"},{"name":"11Program in Medical and Population Genetics and the Cardiovascular Disease Initiative, Broad Institute of Harvard and MIT, Cambridge, MA;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabriel K.","family":"Griffin","sequence":"additional","affiliation":[{"name":"2Broad Institute of Harvard and MIT, Cambridge, MA;"},{"name":"7Department of Pathology, Brigham and Women\u2019s Hospital, Harvard Medical School, Boston, MA;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9597-0477","authenticated-orcid":false,"given":"Siddhartha","family":"Jaiswal","sequence":"additional","affiliation":[{"name":"12Department of Pathology and Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8402-7435","authenticated-orcid":false,"given":"Pradeep","family":"Natarajan","sequence":"additional","affiliation":[{"name":"10Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA;"},{"name":"11Program in Medical and Population Genetics and the Cardiovascular Disease Initiative, Broad Institute of Harvard and MIT, Cambridge, MA;"},{"name":"13Department of Medicine, Harvard Medical School, Boston, MA;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2126-3702","authenticated-orcid":false,"given":"Peter A.","family":"Nigrovic","sequence":"additional","affiliation":[{"name":"4Division of Immunology, Boston Children's Hospital, Boston, MA;"},{"name":"14Division of Rheumatology, Inflammation, Immunity, Department of Medicine, Brigham and Women\u2019s Hospital, Harvard Medical School, Boston, MA; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9672-7746","authenticated-orcid":false,"given":"Deepak A.","family":"Rao","sequence":"additional","affiliation":[{"name":"14Division of Rheumatology, Inflammation, Immunity, Department of Medicine, Brigham and Women\u2019s Hospital, Harvard Medical School, Boston, MA; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0197-5451","authenticated-orcid":false,"given":"Benjamin L.","family":"Ebert","sequence":"additional","affiliation":[{"name":"1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA;"},{"name":"15Howard Hughes Medical Institute, Boston, MA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"234","reference":[{"issue":"6","key":"2022090815231333000_B1","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1186\/ar3199","article-title":"Epidemiology of gout","volume":"12","author":"Roddy","year":"2010","journal-title":"Arthritis Res Ther."},{"issue":"6","key":"2022090815231333000_B2","doi-asserted-by":"crossref","first-page":"991","DOI":"10.1002\/art.40807","article-title":"Contemporary prevalence of gout and hyperuricemia in the United States and decadal trends: the National Health and Nutrition Examination Survey, 2007-2016","volume":"71","author":"Chen-Xu","year":"2019","journal-title":"Arthritis Rheumatol."},{"issue":"7","key":"2022090815231333000_B3","doi-asserted-by":"crossref","first-page":"380","DOI":"10.1038\/s41584-020-0441-1","article-title":"Global epidemiology of gout: prevalence, incidence, treatment patterns and risk factors","volume":"16","author":"Dehlin","year":"2020","journal-title":"Nat Rev Rheumatol."},{"issue":"10287","key":"2022090815231333000_B4","doi-asserted-by":"crossref","first-page":"1843","DOI":"10.1016\/S0140-6736(21)00569-9","article-title":"Gout","volume":"397","author":"Dalbeth","year":"2021","journal-title":"Lancet."},{"issue":"9","key":"2022090815231333000_B5","doi-asserted-by":"crossref","first-page":"1304","DOI":"10.1002\/acr.22585","article-title":"Study for updated gout classification criteria: identification of features to classify gout","volume":"67","author":"Taylor","year":"2015","journal-title":"Arthritis Care Res (Hoboken)."},{"issue":"2","key":"2022090815231333000_B6","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1002\/art.1780150209","article-title":"The influence of temperature on the solubility of monosodium urate","volume":"15","author":"Loeb","year":"1972","journal-title":"Arthritis Rheum."},{"issue":"5","key":"2022090815231333000_B7","doi-asserted-by":"crossref","first-page":"443","DOI":"10.1056\/NEJMcp1001124","article-title":"Clinical practice: gout","volume":"364","author":"Neogi","year":"2011","journal-title":"N Engl J Med."},{"issue":"7081","key":"2022090815231333000_B8","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1038\/nature04516","article-title":"Gout-associated uric acid crystals activate the NALP3 inflammasome","volume":"440","author":"Martinon","year":"2006","journal-title":"Nature."},{"issue":"2","key":"2022090815231333000_B9","doi-asserted-by":"crossref","first-page":"R28","DOI":"10.1186\/ar2143","article-title":"A pilot study of IL-1 inhibition by anakinra in acute gout","volume":"9","author":"So","year":"2007","journal-title":"Arthritis Res Ther."},{"issue":"10","key":"2022090815231333000_B10","doi-asserted-by":"crossref","first-page":"3064","DOI":"10.1002\/art.27600","article-title":"Canakinumab for the treatment of acute flares in difficult-to-treat gouty arthritis: results of a multicenter, phase II, dose-ranging study","volume":"62","author":"So","year":"2010","journal-title":"Arthritis Rheum."},{"issue":"26","key":"2022090815231333000_B11","doi-asserted-by":"crossref","first-page":"2488","DOI":"10.1056\/NEJMoa1408617","article-title":"Age-related clonal hematopoiesis associated with adverse outcomes","volume":"371","author":"Jaiswal","year":"2014","journal-title":"N Engl J Med."},{"issue":"26","key":"2022090815231333000_B12","doi-asserted-by":"crossref","first-page":"2477","DOI":"10.1056\/NEJMoa1409405","article-title":"Clonal hematopoiesis and blood-cancer risk inferred from blood DNA sequence","volume":"371","author":"Genovese","year":"2014","journal-title":"N Engl J Med."},{"issue":"2","key":"2022090815231333000_B13","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1056\/NEJMoa1701719","article-title":"Clonal hematopoiesis and risk of atherosclerotic cardiovascular disease","volume":"377","author":"Jaiswal","year":"2017","journal-title":"N Engl J Med."},{"issue":"6327","key":"2022090815231333000_B14","doi-asserted-by":"crossref","first-page":"842","DOI":"10.1126\/science.aag1381","article-title":"Clonal hematopoiesis associated with TET2 deficiency accelerates atherosclerosis development in mice","volume":"355","author":"Fuster","year":"2017","journal-title":"Science."},{"issue":"3","key":"2022090815231333000_B15","doi-asserted-by":"crossref","first-page":"357","DOI":"10.1182\/blood.2021013531","article-title":"Association of clonal hematopoiesis with chronic obstructive pulmonary disease","volume":"139","author":"Miller","year":"2022","journal-title":"Blood."},{"issue":"12","key":"2022090815231333000_B16","doi-asserted-by":"crossref","first-page":"e20211872","DOI":"10.1084\/jem.20211872","article-title":"Dnmt3a-mutated clonal hematopoiesis promotes osteoporosis","volume":"218","author":"Kim","year":"2021","journal-title":"J Exp Med."},{"issue":"16","key":"2022090815231333000_B17","doi-asserted-by":"crossref","first-page":"2482","DOI":"10.1182\/bloodadvances.2018024729","article-title":"Comorbid and inflammatory characteristics of genetic subtypes of clonal hematopoiesis","volume":"3","author":"Cook","year":"2019","journal-title":"Blood Adv."},{"issue":"1","key":"2022090815231333000_B18","doi-asserted-by":"crossref","first-page":"E5","DOI":"10.3390\/jpm6010005","article-title":"An eMERGE Clinical Center at Partners Personalized Medicine","volume":"6","author":"Smoller","year":"2016","journal-title":"J Pers Med."},{"issue":"7726","key":"2022090815231333000_B19","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1038\/s41586-018-0579-z","article-title":"The UK Biobank resource with deep phenotyping and genomic data","volume":"562","author":"Bycroft","year":"2018","journal-title":"Nature."},{"issue":"22","key":"2022090815231333000_B20","doi-asserted-by":"crossref","first-page":"2867","DOI":"10.1093\/bioinformatics\/btq559","article-title":"Robust relationship inference in genome-wide association studies","volume":"26","author":"Manichaikul","year":"2010","journal-title":"Bioinformatics."},{"issue":"7831","key":"2022090815231333000_B21","doi-asserted-by":"crossref","first-page":"763","DOI":"10.1038\/s41586-020-2819-2","article-title":"Inherited causes of clonal haematopoiesis in 97,691 whole genomes","volume":"586","author":"Bick","year":"2020","journal-title":"Nature."},{"issue":"11","key":"2022090815231333000_B22","doi-asserted-by":"crossref","first-page":"1921","DOI":"10.1038\/s41591-021-01521-4","article-title":"Distinction of lymphoid and myeloid clonal hematopoiesis","volume":"27","author":"Niroula","year":"2021","journal-title":"Nat Med."},{"issue":"5","key":"2022090815231333000_B23","doi-asserted-by":"crossref","first-page":"500","DOI":"10.1158\/2643-3230.BCD-20-0224","article-title":"ZBTB33 is mutated in clonal hematopoiesis and myelodysplastic syndromes and impacts RNA splicing","volume":"2","author":"Beauchamp","year":"2021","journal-title":"Blood Cancer Discov."},{"issue":"7809","key":"2022090815231333000_B24","doi-asserted-by":"crossref","first-page":"434","DOI":"10.1038\/s41586-020-2308-7","article-title":"The mutational constraint spectrum quantified from variation in 141,456 humans","volume":"581","author":"Karczewski","year":"2020","journal-title":"Nature."},{"issue":"5","key":"2022090815231333000_B25","doi-asserted-by":"crossref","first-page":"511","DOI":"10.1038\/nm.3547","article-title":"Aggregated neutrophil extracellular traps limit inflammation by degrading cytokines and chemokines","volume":"20","author":"Schauer","year":"2014","journal-title":"Nat Med."},{"issue":"17","key":"2022090815231333000_B26","doi-asserted-by":"crossref","first-page":"i884","DOI":"10.1093\/bioinformatics\/bty560","article-title":"fastp: an ultra-fast all-in-one FASTQ preprocessor","volume":"34","author":"Chen","year":"2018","journal-title":"Bioinformatics."},{"issue":"1","key":"2022090815231333000_B27","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1093\/bioinformatics\/bts635","article-title":"STAR: ultrafast universal RNA-seq aligner","volume":"29","author":"Dobin","year":"2013","journal-title":"Bioinformatics."},{"issue":"7","key":"2022090815231333000_B28","doi-asserted-by":"crossref","first-page":"923","DOI":"10.1093\/bioinformatics\/btt656","article-title":"featureCounts: an efficient general-purpose program for assigning sequence reads to genomic features","volume":"30","author":"Liao","year":"2014","journal-title":"Bioinformatics."},{"issue":"12","key":"2022090815231333000_B29","doi-asserted-by":"crossref","first-page":"550","DOI":"10.1186\/s13059-014-0550-8","article-title":"Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2","volume":"15","author":"Love","year":"2014","journal-title":"Genome Biol."},{"issue":"5","key":"2022090815231333000_B30","doi-asserted-by":"crossref","first-page":"284","DOI":"10.1089\/omi.2011.0118","article-title":"clusterProfiler: an R package for comparing biological themes among gene clusters","volume":"16","author":"Yu","year":"2012","journal-title":"OMICS."},{"issue":"26","key":"2022090815231333000_B31","doi-asserted-by":"crossref","first-page":"3051","DOI":"10.1182\/blood.2020008206","article-title":"Contribution of clonal hematopoiesis to adult-onset hemophagocytic lymphohistiocytosis","volume":"136","author":"Miller","year":"2020","journal-title":"Blood."},{"issue":"436","key":"2022090815231333000_B32","doi-asserted-by":"crossref","first-page":"eaan8292","DOI":"10.1126\/scitranslmed.aan8292","article-title":"Increased neutrophil extracellular trap formation promotes thrombosis in myeloproliferative neoplasms","volume":"10","author":"Wolach","year":"2018","journal-title":"Sci Transl Med."},{"issue":"2","key":"2022090815231333000_B33","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1161\/CIRCULATIONAHA.119.044362","article-title":"Genetic interleukin 6 signaling deficiency attenuates cardiovascular risk in clonal hematopoiesis","volume":"141","author":"Bick","year":"2020","journal-title":"Circulation."},{"issue":"8","key":"2022090815231333000_B34","doi-asserted-by":"crossref","first-page":"535","DOI":"10.7326\/M18-1167","article-title":"Relationship of interleukin-1\u03b2 blockade with incident gout and serum uric acid levels: exploratory analysis of a randomized controlled trial","volume":"169","author":"Solomon","year":"2018","journal-title":"Ann Intern Med."}],"container-title":["Blood"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/ashpublications.org\/blood\/article-pdf\/140\/10\/1094\/1919007\/bloodbld2022015384.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/ashpublications.org\/blood\/article-pdf\/140\/10\/1094\/1919007\/bloodbld2022015384.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,9,8]],"date-time":"2022-09-08T11:25:23Z","timestamp":1662636323000},"score":1,"resource":{"primary":{"URL":"https:\/\/ashpublications.org\/blood\/article\/140\/10\/1094\/485603\/TET2-mutant-clonal-hematopoiesis-and-risk-of-gout"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,9,8]]},"references-count":34,"journal-issue":{"issue":"10","published-print":{"date-parts":[[2022,9,8]]}},"URL":"https:\/\/doi.org\/10.1182\/blood.2022015384","relation":{},"ISSN":["0006-4971","1528-0020"],"issn-type":[{"value":"0006-4971","type":"print"},{"value":"1528-0020","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,9,8]]}}}