{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,19]],"date-time":"2026-05-19T18:06:42Z","timestamp":1779214002627,"version":"3.51.4"},"reference-count":100,"publisher":"American Society for Clinical Investigation","issue":"14","license":[{"start":{"date-parts":[[2025,7,15]],"date-time":"2025-07-15T00:00:00Z","timestamp":1752537600000},"content-version":"vor","delay-in-days":54,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"NHMRC Australia","award":["APP1056689"],"award-info":[{"award-number":["APP1056689"]}]},{"name":"NHMRC Australia","award":["1172853"],"award-info":[{"award-number":["1172853"]}]},{"name":"Wellcome Trust Fellowship in Public Health and Tropical Medicine to NTTT","award":["206724\/Z\/17\/Z"],"award-info":[{"award-number":["206724\/Z\/17\/Z"]}]},{"name":"Wellcome Trust to Vietnam Africa Asia Programme to GT","award":["106680\/B\/14\/Z"],"award-info":[{"award-number":["106680\/B\/14\/Z"]}]},{"name":"NIH","award":["U19AI162583"],"award-info":[{"award-number":["U19AI162583"]}]},{"name":"NIH","award":["4R33AI138272"],"award-info":[{"award-number":["4R33AI138272"]}]},{"name":"NIH","award":["K24AI37310"],"award-info":[{"award-number":["K24AI37310"]}]},{"name":"NIH","award":["5U19AI135990"],"award-info":[{"award-number":["5U19AI135990"]}]},{"name":"Vietnam Major Overseas Program","award":["089276\/Z\/09\/Z"],"award-info":[{"award-number":["089276\/Z\/09\/Z"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,7,15]]},"abstract":"<jats:p>\n                    Immune and clinical outcomes to\n                    <jats:italic>Mycobacterium tuberculosis<\/jats:italic>\n                    (Mtb) infection vary greatly between individuals, yet the underlying genetic and cellular mechanisms driving this heterogeneity remain poorly understood. We performed a cellular genome-wide association study to identify genetic variants associated with Mtb-induced monocyte transcriptional expression of\n                    <jats:italic>IL1B<\/jats:italic>\n                    ,\n                    <jats:italic>IL6<\/jats:italic>\n                    ,\n                    <jats:italic>TNF<\/jats:italic>\n                    , and\n                    <jats:italic>IFNB1<\/jats:italic>\n                    via RNA-Seq in a Ugandan cohort. Significantly associated variants were assessed for transferability in an independent Seattle cohort, further validated in vitro, and assessed for clinical phenotype associations. We identified 77 loci suggestively associated with Mtb-induced cytokine expression in monocytes in Uganda. SNPs associated with Mtb-induced\n                    <jats:italic>TNF<\/jats:italic>\n                    were enriched within \u03b1-linolenic acid metabolism pathway genes, which was validated in vitro using PLA2 inhibitors. Four loci maintained significant associations in Seattle. We validated a cytokine effect with siRNA knockdown for two of these loci, which mapped to the genes\n                    <jats:italic>SLIT3<\/jats:italic>\n                    and\n                    <jats:italic>SLC1A1<\/jats:italic>\n                    . Furthermore, exogenous treatment of macrophages with SLIT3 enhanced Mtb intracellular replication. Finally,\n                    <jats:italic>SLC1A1<\/jats:italic>\n                    and\n                    <jats:italic>SLIT3<\/jats:italic>\n                    variants were associated with susceptibility to tuberculous meningitis and subsequent survival, respectively, in a Vietnamese cohort. In summary, we identified multiple variants and pathways associated with Mtb-induced cytokine transcriptional responses that were validated in vitro and were associated with clinical tuberculosis susceptibility.\n                  <\/jats:p>","DOI":"10.1172\/jci179822","type":"journal-article","created":{"date-parts":[[2025,5,22]],"date-time":"2025-05-22T12:00:12Z","timestamp":1747915212000},"source":"Crossref","is-referenced-by-count":1,"title":["Myeloid cell genome-wide screen identifies variants associated with Mycobacterium tuberculosis\u2013induced cytokine transcriptional responses"],"prefix":"10.1172","volume":"135","author":[{"given":"Joshua J.","family":"Ivie","sequence":"first","affiliation":[{"name":"Department of Global Health and"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kimberly A.","family":"Dill-McFarland","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Washington, Seattle, Washington, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7669-2803","authenticated-orcid":true,"given":"Jason D.","family":"Simmons","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Washington, Seattle, Washington, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Glenna J.","family":"Peterson","sequence":"additional","affiliation":[{"name":"Department of Global Health and"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Penelope H.","family":"Benchek","sequence":"additional","affiliation":[{"name":"Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, Ohio, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Harriet","family":"Mayanja-Kizza","sequence":"additional","affiliation":[{"name":"Department of Medicine, School of Medicine, Makerere University, Kampala, Uganda."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lily E.","family":"Veith","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Washington, Seattle, Washington, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Moeko","family":"Agata","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Washington, Seattle, Washington, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dang T.M.","family":"Ha","sequence":"additional","affiliation":[{"name":"Pham Ngoc Thanh Hospital, Ho Chi Minh City, Vietnam."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ho D.T.","family":"Nghia","sequence":"additional","affiliation":[{"name":"Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam."},{"name":"Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam."},{"name":"Pham Ngoc Thach University of Medicine, Ho Chi Minh City, Vietnam."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"W. Henry","family":"Boom","sequence":"additional","affiliation":[{"name":"Department of Medicine, Case Western Reserve University, Cleveland, Ohio, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Catherine M.","family":"Stein","sequence":"additional","affiliation":[{"name":"Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, Ohio, USA."},{"name":"Department of Medicine, Case Western Reserve University, Cleveland, Ohio, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chiea C.","family":"Khor","sequence":"additional","affiliation":[{"name":"Genome Institute of Singapore, A-STAR, Singapore."},{"name":"Singapore Eye Research Institute, Singapore National Eye Centre and Eye ACP, Duke\u2013National University of Singapore, Singapore."},{"name":"Department of Biochemistry, National University of Singapore, Singapore."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Guy E.","family":"Thwaites","sequence":"additional","affiliation":[{"name":"Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam."},{"name":"Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hoang T.","family":"Hai","sequence":"additional","affiliation":[{"name":"Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam."},{"name":"Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nguyen T.T.","family":"Thuong","sequence":"additional","affiliation":[{"name":"Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam."},{"name":"Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xuling","family":"Chang","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases, University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Parkville, Victoria, Australia."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sarah J.","family":"Dunstan","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases, University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Parkville, Victoria, Australia."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Thomas R.","family":"Hawn","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Washington, Seattle, Washington, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"232","published-online":{"date-parts":[[2025,5,22]]},"reference":[{"key":"B1","unstructured":"World Health Organization. Global Tuberculosis Report 2023. https:\/\/www.who.int\/teams\/global-tuberculosis-programme\/tb-reports\/global-tuberculosis-report-2023 Updated November 7, 2023. Accessed December 12, 2023"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1038\/s41577-018-0025-3"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1155\/2013\/828939"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1038\/ng.2744"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1111\/imr.12264"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1164\/arrd.1978.117.4.621"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1164\/ajrccm.149.3.8118628"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-019-11664-1"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1016\/j.ebiom.2021.103727"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1086\/375249"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1007\/s40142-017-0130-9"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1038\/ng.3248"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1038\/ng.3498"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1038\/ng.1080"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1038\/ng.639"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1002\/mco2.250"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1007\/s00439-016-1633-2"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddt462"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2350-13-5"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.immunol.20.081501.125851"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1003424"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1016\/j.chom.2018.07.007"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1038\/nm.4139"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1126\/science.1246980"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1016\/j.jgg.2023.01.002"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2009.07.012"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1714765115"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2015.02.046"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1038\/s41423-020-0502-z"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1111\/sji.12136"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1054\/tuld.1998.0009"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1084\/jem.189.12.1863"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1202688"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1016\/1074-7613(95)90001-2"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.168.9.4620"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1900108"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1016\/j.meegid.2021.105166"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1128\/iai.65.11.4843-4849.1997"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.091096998"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1038\/nature09247"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1128\/msphere.00159-22"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1172\/JCI140073"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-016-0974-4"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkac1010"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1016\/j.thromres.2022.10.016"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1016\/j.isci.2021.103337"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1111\/aji.12181"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0183854"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.054007"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.1038\/s41422-022-00689-9"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.1006\/bbrc.2000.3106"},{"key":"B52","doi-asserted-by":"publisher","DOI":"10.1080\/15548627.2017.1376160"},{"key":"B53","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20200887"},{"key":"B54","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pcbi.1004219"},{"key":"B55","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0506580102"},{"key":"B56","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btr260"},{"key":"B57","doi-asserted-by":"publisher","DOI":"10.1016\/j.apjtm.2016.01.021"},{"key":"B58","doi-asserted-by":"publisher","DOI":"10.3390\/molecules27010152"},{"key":"B59","doi-asserted-by":"publisher","DOI":"10.1039\/D2SC04307F"},{"key":"B60","doi-asserted-by":"publisher","DOI":"10.1093\/oxfordjournals.jbchem.a003101"},{"key":"B61","doi-asserted-by":"publisher","DOI":"10.1038\/s42255-021-00482-9"},{"key":"B62","doi-asserted-by":"publisher","DOI":"10.1242\/dev.128.24.5031"},{"key":"B63","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.0903898"},{"key":"B64","doi-asserted-by":"publisher","DOI":"10.1038\/nn.3893"},{"key":"B65","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-021-00924-w"},{"key":"B66","doi-asserted-by":"publisher","DOI":"10.1038\/hgv.2018.8"},{"key":"B67","doi-asserted-by":"publisher","DOI":"10.1128\/msystems.00628-24"},{"key":"B68","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1000229"},{"key":"B69","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1507062"},{"key":"B70","doi-asserted-by":"publisher","DOI":"10.1186\/s12879-018-3033-9"},{"key":"B71","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa040573"},{"key":"B72","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.166.12.7469"},{"key":"B73","doi-asserted-by":"publisher","DOI":"10.1002\/jlb.54.2.105"},{"key":"B74","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.175.10.6924"},{"key":"B75","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.923265"},{"key":"B76","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20080767"},{"key":"B77","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2010.02.013"},{"key":"B78","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2011.12.023"},{"key":"B79","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1302021"},{"key":"B80","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20101138"},{"key":"B81","doi-asserted-by":"publisher","DOI":"10.1093\/infdis\/jiad126"},{"key":"B82","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2024852118"},{"key":"B83","doi-asserted-by":"publisher","DOI":"10.1016\/j.ebiom.2021.103614"},{"key":"B84","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.753092"},{"key":"B85","doi-asserted-by":"publisher","DOI":"10.1111\/epi.13397"},{"key":"B86","doi-asserted-by":"publisher","DOI":"10.1038\/ng.3540"},{"key":"B87","doi-asserted-by":"publisher","DOI":"10.1093\/nargab\/lqaa078"},{"key":"B88","doi-asserted-by":"publisher","DOI":"10.1186\/gb-2014-15-2-r29"},{"key":"B89","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1010387"},{"key":"B90","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-021-03205-y"},{"key":"B91","doi-asserted-by":"publisher","DOI":"10.1038\/ng.3656"},{"key":"B92","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btz567"},{"key":"B93","doi-asserted-by":"publisher","DOI":"10.1186\/s13742-015-0047-8"},{"key":"B94","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btad279"},{"key":"B95","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btw643"},{"key":"B96","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkac1000"},{"key":"B97","doi-asserted-by":"publisher","DOI":"10.1101\/gr.1239303"},{"key":"B98","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btx513"},{"key":"B99","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-018-0184-y"},{"key":"B100","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2020.06.003"}],"container-title":["Journal of Clinical Investigation"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.jci.org\/articles\/view\/179822\/files\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,19]],"date-time":"2026-05-19T17:16:20Z","timestamp":1779210980000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.jci.org\/articles\/view\/179822"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,5,22]]},"references-count":100,"journal-issue":{"issue":"14","published-online":{"date-parts":[[2025,5,20]]},"published-print":{"date-parts":[[2025,7,15]]}},"alternative-id":["10.1172\/JCI179822"],"URL":"https:\/\/doi.org\/10.1172\/jci179822","relation":{},"ISSN":["1558-8238"],"issn-type":[{"value":"1558-8238","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,5,22]]},"article-number":"e179822"}}