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Immunol."],"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>The heterogeneity of outcomes after <jats:italic>Mycobacterium tuberculosis<\/jats:italic> (Mtb) exposure is a conundrum associated with millennia of host-pathogen co-evolution. We hypothesized that human myeloid cells contain genetically encoded, Mtb-specific responses that regulate critical steps in tuberculosis (TB) pathogenesis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We mapped genome-wide expression quantitative trait loci (eQTLs) in Mtb-infected monocytes with RNAseq from 80 Ugandan household contacts of pulmonary TB cases to identify monocyte-specific, Mtb-dependent eQTLs and their association with cytokine expression and clinical resistance to tuberculin skin test (TST) and interferon-\u03b3 release assay (IGRA) conversion.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>cis-eQTLs (n=1,567) were identified in Mtb-infected monocytes (FDR&amp;lt;0.01), including 29 eQTLs in 16 genes which were Mtb-dependent (significant for Mtb:genotype interaction [FDR&amp;lt;0.1], but not classified as eQTL in uninfected condition [FDR\u22650.01]). A subset of eQTLs were associated with Mtb-induced cytokine expression (n=8) and\/or clinical resistance to TST\/IGRA conversion (n=1). Expression of <jats:italic>BMP6<\/jats:italic>, an Mtb-dependent eQTL gene, was associated with <jats:italic>IFNB1<\/jats:italic> induction in Mtb-infected and DNA ligand-induced cells. Network and enrichment analyses identified fatty acid metabolism as a pathway associated with eQTL genes.<\/jats:p><\/jats:sec><jats:sec><jats:title>Discussion<\/jats:title><jats:p>These findings suggest that monocyte genes contain Mtb-dependent eQTLs, including a subset associated with cytokine expression and\/or clinical resistance to TST\/IGRA conversion, providing insight into immunogenetic pathways regulating susceptibility to Mtb infection and TB pathogenesis.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2024.1359178","type":"journal-article","created":{"date-parts":[[2024,3,7]],"date-time":"2024-03-07T04:25:20Z","timestamp":1709785520000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":8,"title":["Mycobacterium tuberculosis-dependent monocyte expression quantitative trait loci, cytokine production, and TB pathogenesis"],"prefix":"10.3389","volume":"15","author":[{"given":"Hyejeong","family":"Hong","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kimberly A.","family":"Dill-McFarland","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jason D.","family":"Simmons","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Glenna J.","family":"Peterson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Penelope","family":"Benchek","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Harriet","family":"Mayanja-Kizza","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"W. 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