{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T11:19:33Z","timestamp":1791976773121,"version":"4.4.0"},"reference-count":35,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"2","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation"],"published-print":{"date-parts":[[2020,1,14]]},"abstract":"<jats:sec>\n                    <jats:title>Background:<\/jats:title>\n                    <jats:p>\n                      Clonal hematopoiesis of indeterminate potential (CHIP) refers to clonal expansion of hematopoietic stem cells attributable to acquired leukemic mutations in genes such as\n                      <jats:italic>DNMT3A<\/jats:italic>\n                      or\n                      <jats:italic>TET2<\/jats:italic>\n                      . In humans, CHIP associates with prevalent myocardial infarction. In mice, CHIP accelerates atherosclerosis and increases IL-6\/IL-1\u03b2 expression, raising the hypothesis that IL-6 pathway antagonism in CHIP carriers would decrease cardiovascular disease (CVD) risk.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods:<\/jats:title>\n                    <jats:p>\n                      We analyzed exome sequences from 35 416 individuals in the UK Biobank without prevalent CVD, to identify participants with\n                      <jats:italic>DNMT3A<\/jats:italic>\n                      or\n                      <jats:italic>TET2<\/jats:italic>\n                      CHIP. We used the\n                      <jats:italic>IL6R<\/jats:italic>\n                      p.Asp358Ala coding mutation as a genetic proxy for IL-6 inhibition. We tested the association of CHIP status with incident CVD events (myocardial infarction, coronary revascularization, stroke, or death), and whether it was modified by\n                      <jats:italic>IL6R<\/jats:italic>\n                      p.Asp358Ala.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results:<\/jats:title>\n                    <jats:p>\n                      We identified 1079 (3.0%) individuals with CHIP, including 432 (1.2%) with large clones (allele fraction &gt;10%). During 6.9-year median follow-up, CHIP associated with increased incident CVD event risk (hazard ratio, 1.27 [95% CI, 1.04\u20131.56],\n                      <jats:italic>P<\/jats:italic>\n                      =0.019), with greater risk from large CHIP clones (hazard ratio, 1.59 [95% CI, 1.21\u20132.09],\n                      <jats:italic>P<\/jats:italic>\n                      &lt;0.001).\n                      <jats:italic>IL6R<\/jats:italic>\n                      p.Asp358Ala attenuated CVD event risk among participants with large CHIP clones (hazard ratio, 0.46 [95% CI, 0.29\u20130.73],\n                      <jats:italic>P<\/jats:italic>\n                      &lt;0.001) but not in individuals without CHIP (hazard ratio, 0.95 [95% CI, 0.89\u20131.01],\n                      <jats:italic>P<\/jats:italic>\n                      =0.08;\n                      <jats:italic>P<\/jats:italic>\n                      <jats:sub>interaction<\/jats:sub>\n                      =0.003). In 9951 independent participants, the association of CHIP status with myocardial infarction similarly varied by\n                      <jats:italic>IL6R<\/jats:italic>\n                      p.Asp358Ala (\n                      <jats:italic>P<\/jats:italic>\n                      <jats:sub>interaction<\/jats:sub>\n                      =0.036).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions:<\/jats:title>\n                    <jats:p>CHIP is associated with increased risk of incident CVD. Among carriers of large CHIP clones, genetically reduced IL-6 signaling abrogated this risk.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/circulationaha.119.044362","type":"journal-article","created":{"date-parts":[[2019,11,11]],"date-time":"2019-11-11T05:00:35Z","timestamp":1573448435000},"page":"124-131","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":432,"title":["Genetic Interleukin 6 Signaling Deficiency Attenuates Cardiovascular Risk in Clonal Hematopoiesis"],"prefix":"10.1161","volume":"141","author":[{"given":"Alexander G.","family":"Bick","sequence":"first","affiliation":[{"name":"Cardiovascular Research Center (A.G.B., J.P.P., P.N.), Massachusetts General Hospital, Boston."},{"name":"Center for Genomic Medicine (A.G.B., J.P.P., S.K., P.N.), Massachusetts General Hospital, Boston."},{"name":"Department of Medicine (A.G.B., J.P.P., S.K., P.N.), Harvard Medical School, Boston, MA."},{"name":"Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge (A.G.B., J.P.P., G.K.G., N.G., S.G., S.K., P.N.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James P.","family":"Pirruccello","sequence":"additional","affiliation":[{"name":"Cardiovascular Research Center (A.G.B., J.P.P., P.N.), Massachusetts General Hospital, Boston."},{"name":"Center for Genomic Medicine (A.G.B., J.P.P., S.K., P.N.), Massachusetts General Hospital, Boston."},{"name":"Department of Medicine (A.G.B., J.P.P., S.K., P.N.), Harvard Medical School, Boston, MA."},{"name":"Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge (A.G.B., J.P.P., G.K.G., N.G., S.G., S.K., P.N.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabriel K.","family":"Griffin","sequence":"additional","affiliation":[{"name":"Department of Pathology (G.K.G.), Harvard Medical School, Boston, MA."},{"name":"Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge (A.G.B., J.P.P., G.K.G., N.G., S.G., S.K., P.N.)."},{"name":"Department of Pathology (G.K.G.), Brigham and Women\u2019s Hospital, Boston, MA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Namrata","family":"Gupta","sequence":"additional","affiliation":[{"name":"Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge (A.G.B., J.P.P., G.K.G., N.G., S.G., S.K., P.N.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stacey","family":"Gabriel","sequence":"additional","affiliation":[{"name":"Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge (A.G.B., J.P.P., G.K.G., N.G., S.G., S.K., P.N.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Danish","family":"Saleheen","sequence":"additional","affiliation":[{"name":"Department of Biostatistics and Epidemiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia (D.S.)."},{"name":"Center for Non-Communicable Diseases, Karachi, Pakistan (D.S.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Libby","sequence":"additional","affiliation":[{"name":"Division of Cardiology (P.L.), Brigham and Women\u2019s Hospital, Boston, MA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sekar","family":"Kathiresan","sequence":"additional","affiliation":[{"name":"Center for Genomic Medicine (A.G.B., J.P.P., S.K., P.N.), Massachusetts General Hospital, Boston."},{"name":"Department of Medicine (A.G.B., J.P.P., S.K., P.N.), Harvard Medical School, Boston, MA."},{"name":"Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge (A.G.B., J.P.P., G.K.G., N.G., S.G., S.K., P.N.)."},{"name":"Verve Therapeutics, Cambridge, MA (S.K.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pradeep","family":"Natarajan","sequence":"additional","affiliation":[{"name":"Cardiovascular Research Center (A.G.B., J.P.P., P.N.), Massachusetts General Hospital, Boston."},{"name":"Center for Genomic Medicine (A.G.B., J.P.P., S.K., P.N.), Massachusetts General Hospital, Boston."},{"name":"Department of Medicine (A.G.B., J.P.P., S.K., P.N.), Harvard Medical School, Boston, MA."},{"name":"Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge (A.G.B., J.P.P., G.K.G., N.G., S.G., S.K., P.N.)."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2015-03-631747"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1408617"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1038\/nm.3733"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1409405"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.3004315"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1701719"},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.aag1381"},{"key":"e_1_3_4_9_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2017.12.037"},{"key":"e_1_3_4_10_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1003444"},{"key":"e_1_3_4_11_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(12)60110-X"},{"key":"e_1_3_4_12_2","doi-asserted-by":"publisher","DOI":"10.1001\/jamacardio.2018.2287"},{"key":"e_1_3_4_13_2","article-title":"Whole exome sequencing and characterization of coding variation in 49,960 individuals in the UK Biobank.","author":"van Hout CV","year":"2019","unstructured":"van Hout, CV, Tachmazidou, I, Backman, JD, Hoffman, JX, Ye, B, Pandey, AK, Gonzaga-Jauregui, C, Khalid, S, Liu, D, Banerjee, N, et al. Whole exome sequencing and characterization of coding variation in 49,960 individuals in the UK Biobank. bioRxiv 2019. https:\/\/doi.org\/10.1101\/572347. Accessed October 10, 2019.","journal-title":"bioRxiv"},{"key":"e_1_3_4_14_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-018-0579-z"},{"key":"e_1_3_4_15_2","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btq559"},{"key":"e_1_3_4_16_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2018.08.004"},{"key":"e_1_3_4_17_2","doi-asserted-by":"publisher","DOI":"10.1007\/s10654-009-9334-y"},{"key":"e_1_3_4_18_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature22034"},{"key":"e_1_3_4_19_2","doi-asserted-by":"publisher","DOI":"10.1038\/nbt.2514"},{"key":"e_1_3_4_20_2","article-title":"Genetics of 38 blood and urine biomarkers in the UK Biobank.","author":"Sinnott-Armstrong N","year":"2019","unstructured":"Sinnott-Armstrong, N, Tanigawa, Y, Amar, D, Mars, NJ, Aguirre, M, Venkataraman, GR, Wainberg, M, Ollila, HM, Pirruccello, JP, Qian, J, et al. Genetics of 38 blood and urine biomarkers in the UK Biobank. bioRxiv 2019. https:\/\/doi.org\/10.1101\/660506. Accessed October 10, 2019.","journal-title":"bioRxiv"},{"key":"e_1_3_4_21_2","doi-asserted-by":"publisher","DOI":"10.1194\/jlr.M800140-JLR200"},{"key":"e_1_3_4_22_2","doi-asserted-by":"publisher","DOI":"10.1093\/aje\/kwm324"},{"key":"e_1_3_4_23_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2018.09.009"},{"key":"e_1_3_4_24_2","doi-asserted-by":"publisher","DOI":"10.1080\/01621459.1985.10478157"},{"key":"e_1_3_4_25_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMp1500523"},{"key":"e_1_3_4_26_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2017-02-769869"},{"key":"e_1_3_4_27_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-018-0321-x"},{"key":"e_1_3_4_28_2","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms12484"},{"key":"e_1_3_4_29_2","article-title":"The evolutionary dynamics and fitness landscape of clonal haematopoiesis.","author":"Watson CJ","year":"2019","unstructured":"Watson, CJ, Papula, A, Poon, YPG, Wong, WH, Young, AL, Druley, TE, Fisher, DS, Blundell, JR. The evolutionary dynamics and fitness landscape of clonal haematopoiesis. bioRxiv 2019. https:\/\/doi.org\/10.1101\/569566. Accessed October 10, 2019.","journal-title":"bioRxiv"},{"key":"e_1_3_4_30_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.118.313225"},{"key":"e_1_3_4_31_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1707914"},{"key":"e_1_3_4_32_2","doi-asserted-by":"publisher","DOI":"10.1016\/0008-8749(89)90095-6"},{"key":"e_1_3_4_33_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI114498"},{"key":"e_1_3_4_34_2","doi-asserted-by":"publisher","DOI":"10.1161\/circ.138.suppl_1.15111"},{"key":"e_1_3_4_35_2","article-title":"Cardiovascular safety of tocilizumab versus etanercept in rheumatoid arthritis: a randomized controlled trial.","author":"Giles JT","year":"2019","unstructured":"Giles, JT, Sattar, N, Gabriel, S, Ridker, PM, Gay, S, Warne, C, Musselman, D, Brockwell, L, Shittu, E, Klearman, M, et al. Cardiovascular safety of tocilizumab versus etanercept in rheumatoid arthritis: a randomized controlled trial. Arthritis Rheumatol. 2019. https:\/\/doi.org\/10.1002\/art.41095. Accessed October 10, 2019.","journal-title":"Arthritis Rheumatol"},{"key":"e_1_3_4_36_2","doi-asserted-by":"crossref","unstructured":"Bick AG Weinstock JS Nandakumar SK Fulco CP Leventhal MJ Bao EL Nasser J Zekavat SM Szeto MD Laurie C et al. Inherited causes of clonal hematopoiesis of indeterminate potential in TOPMed whole genomes. bioRxiv 2019. http:\/\/dx.doi.org\/10.1101\/782748. Accessed October 10 2019.","DOI":"10.1101\/782748"}],"container-title":["Circulation"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.ahajournals.org\/doi\/full\/10.1161\/CIRCULATIONAHA.119.044362","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,5,13]],"date-time":"2024-05-13T04:47:39Z","timestamp":1715575659000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.ahajournals.org\/doi\/10.1161\/CIRCULATIONAHA.119.044362"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,1,14]]},"references-count":35,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2020,1,14]]}},"alternative-id":["10.1161\/CIRCULATIONAHA.119.044362"],"URL":"https:\/\/doi.org\/10.1161\/circulationaha.119.044362","relation":{},"ISSN":["0009-7322","1524-4539"],"issn-type":[{"value":"0009-7322","type":"print"},{"value":"1524-4539","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,1,14]]},"assertion":[{"value":"2019-10-11","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2019-11-04","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2019-11-11","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}