{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T18:01:26Z","timestamp":1790791286817,"version":"4.1.0"},"reference-count":46,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2021,12,10]],"date-time":"2021-12-10T00:00:00Z","timestamp":1639094400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Eur J Immunol"],"published-print":{"date-parts":[[2022,3]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Innate immune cells are able to build memory characteristics via a process termed \u201ctrained immunity.\u201d Host factors that influence the magnitude of the individual trained immunity response remain largely unknown. Using an integrative genomics approach, our study aimed to prioritize and understand the role of specific genes in trained immunity responses. In vitro\u2010induced trained immunity responses were assessed in two independent population\u2010based cohorts of healthy individuals, the 300 Bacillus Calmette\u2010Gu\u00e9rin (300BCG;\n                    <jats:italic>n<\/jats:italic>\n                    = 267) and 200 Functional Genomics (200FG;\n                    <jats:italic>n<\/jats:italic>\n                    = 110) cohorts from the Human Functional Genomics Project. Genetic loci that influence cytokine responses upon trained immunity were identified by conducting a meta\u2010analysis of QTLs identified in the 300BCG and 200FG cohorts. From the identified QTL loci, we functionally validated the role of PI3K\u2010Akt signaling pathway and two genes that belong to the family of Siglec receptors (Siglec\u20105 and Siglec\u201014). Furthermore, we identified the H3K9 histone demethylases of the KDM4 family as major regulators of trained immunity responses. These data pinpoint an important role of metabolic and epigenetic processes in the regulation of trained immunity responses, and these findings may open new avenues for vaccine design and therapeutic interventions.\n                  <\/jats:p>","DOI":"10.1002\/eji.202149577","type":"journal-article","created":{"date-parts":[[2021,11,26]],"date-time":"2021-11-26T04:38:14Z","timestamp":1637901494000},"page":"431-446","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":49,"title":["An integrative genomics approach identifies KDM4 as a modulator of trained immunity"],"prefix":"10.1002","volume":"52","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8884-8417","authenticated-orcid":false,"given":"Simone J.C.F.M.","family":"Moorlag","sequence":"first","affiliation":[{"name":"Department of Internal Medicine and Radboud Center for Infectious Diseases Radboud University Medical Center  Nijmegen The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5852-6801","authenticated-orcid":false,"given":"Vasiliki","family":"Matzaraki","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine and Radboud Center for Infectious Diseases Radboud University Medical Center  Nijmegen The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jelmer H.","family":"van Puffelen","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine and Radboud Center for Infectious Diseases Radboud University Medical Center  Nijmegen The Netherlands"},{"name":"Department for Health Evidence Radboud University Medical Center  Nijmegen The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charlotte","family":"van der Heijden","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine and Radboud Center for Infectious Diseases Radboud University Medical Center  Nijmegen The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sam","family":"Keating","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine and Radboud Center for Infectious Diseases Radboud University Medical Center  Nijmegen The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laszlo","family":"Groh","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine and Radboud Center for Infectious Diseases Radboud University Medical Center  Nijmegen The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rutger Jan","family":"R\u00f6ring","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine and Radboud Center for Infectious Diseases Radboud University Medical Center  Nijmegen The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olivier B.","family":"Bakker","sequence":"additional","affiliation":[{"name":"Department of Genetics University Medical Center Groningen University of Groningenor  Groningen The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vera P.","family":"Mourits","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine and Radboud Center for Infectious Diseases Radboud University Medical Center  Nijmegen The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valerie A.C.M.","family":"Koeken","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine and Radboud Center for Infectious Diseases Radboud University Medical Center  Nijmegen The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"L. Charlotte J.","family":"de Bree","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine and Radboud Center for Infectious Diseases Radboud University Medical Center  Nijmegen The Netherlands"},{"name":"Research Center for Vitamins and Vaccines Bandim Health Project Statens Serum Institut  Copenhagen Denmark"},{"name":"Odense Patient Data Explorative Network University of Southern Denmark\/Odense University Hospital  Odense Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sanne P.","family":"Smeekens","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine and Radboud Center for Infectious Diseases Radboud University Medical Center  Nijmegen The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marije","family":"Oosting","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine and Radboud Center for Infectious Diseases Radboud University Medical Center  Nijmegen The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ra\u00fal Aguirre","family":"Gamboa","sequence":"additional","affiliation":[{"name":"Department of Genetics University Medical Center Groningen University of Groningenor  Groningen The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Niels P.","family":"Riksen","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine and Radboud Center for Infectious Diseases Radboud University Medical Center  Nijmegen The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ramnik J.","family":"Xavier","sequence":"additional","affiliation":[{"name":"The Broad Institute of MIT and Harvard  Cambridge Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cisca","family":"Wijmenga","sequence":"additional","affiliation":[{"name":"Department of Genetics University Medical Center Groningen University of Groningenor  Groningen The Netherlands"},{"name":"K.G. Jebsen Coeliac Disease Research Centre Department of Immunology University of Oslo  Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vinod","family":"Kumar","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine and Radboud Center for Infectious Diseases Radboud University Medical Center  Nijmegen The Netherlands"},{"name":"Department of Genetics University Medical Center Groningen University of Groningenor  Groningen The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Reinout","family":"van Crevel","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine and Radboud Center for Infectious Diseases Radboud University Medical Center  Nijmegen The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Boris","family":"Novakovic","sequence":"additional","affiliation":[{"name":"Epigenetics Murdoch Children's Research Institute Royal Children's Hospital, and Department of Paediatrics University of Melbourne  Parkville Victoria Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leo A.B.","family":"Joosten","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine and Radboud Center for Infectious Diseases Radboud University Medical Center  Nijmegen The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine and Radboud Center for Infectious Diseases Radboud University Medical Center  Nijmegen The Netherlands"},{"name":"Department of Computational Biology for Individualised Infection Medicine Centre for Individualised Infection Medicine Helmholtz Centre for Infection Research Hannover Medical School  Hannover Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2421-6052","authenticated-orcid":false,"given":"Mihai G.","family":"Netea","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine and Radboud Center for Infectious Diseases Radboud University Medical Center  Nijmegen The Netherlands"},{"name":"Department for Genomics &amp; Immunoregulation Life and Medical Sciences Institute (LIMES) University of Bonn  Bonn Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2021,12,10]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2006.02.015"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.aaf1098"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.chom.2011.04.006"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.chom.2012.06.006"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1202870109"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.chom.2017.12.010"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2016.11.011"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2017.11.034"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1251086"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2016.10.008"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-019-08659-3"},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1250684"},{"key":"e_1_2_11_14_1","doi-asserted-by":"publisher","DOI":"10.1128\/CVI.00349-16"},{"key":"e_1_2_11_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2016.09.034"},{"key":"e_1_2_11_16_1","doi-asserted-by":"publisher","DOI":"10.1038\/nri2056"},{"key":"e_1_2_11_17_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M502041200"},{"key":"e_1_2_11_18_1","doi-asserted-by":"publisher","DOI":"10.1096\/fj.06-5800com"},{"key":"e_1_2_11_19_1","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20131853"},{"key":"e_1_2_11_20_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrd4154"},{"key":"e_1_2_11_21_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms3035"},{"key":"e_1_2_11_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2012.11.006"},{"key":"e_1_2_11_23_1","doi-asserted-by":"publisher","DOI":"10.35841\/medical-oncology.1.2.34-40"},{"key":"e_1_2_11_24_1","first-page":"680","article-title":"GM\u2010CSF and IL\u20103 Modulate Human Monocyte TNF\u2010\u03b1 Production and Renewal in In Vitro Models of Trained Immunity","volume":"7","author":"Borriello F.","year":"2016","journal-title":"Front. 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