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Many of the genetic variants within or near <jats:italic>TNFRSF1A<\/jats:italic> that have been associated with disease through genome-wide association studies (GWAS) lie in non-coding regions of the genome. Understanding the functional consequences of these genetic variants is limited by incomplete understanding of <jats:italic>TNFRSF1A<\/jats:italic> gene regulation, including for specific cellular contexts relevant to inflammation and immunity such as macrophages. This work used CRISPR\/Cas9 in human induced pluripotent stem cells followed by differentiation into macrophages to investigate putative regulatory elements in the <jats:italic>TNFRSF1A<\/jats:italic> gene locus. Through gene editing, with functional genomic readouts including the assay for transposase-accessible chromatin using sequencing (ATAC-Seq), chromatin immunoprecipitation with sequencing (ChIP-Seq), and RNA-Seq to assess the consequences of these edits, we present evidence for an enhancer of <jats:italic>TNFRSF1A<\/jats:italic> contained within an intron of the gene. Understanding gene regulation and the genomic context in which GWAS variants lie could bring us closer to deconvoluting the genetic basis of common disease aetiology and uncover effective drug targets.<\/jats:p>","DOI":"10.1038\/s41598-025-18077-9","type":"journal-article","created":{"date-parts":[[2025,10,7]],"date-time":"2025-10-07T13:41:55Z","timestamp":1759844515000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Evidence for enhancer activity in intron 1 of TNFRSF1A using CRISPR\/Cas9 in human induced pluripotent stem cell-derived macrophages"],"prefix":"10.1038","volume":"15","author":[{"given":"Julie A.","family":"Osgood","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew C.","family":"Brown","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katie L.","family":"Burnham","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olga","family":"Mielczarek","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabriele","family":"Migliorini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chwen","family":"Tay","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ping","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Madeleine H.","family":"Palmer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ben","family":"Davies","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sally A.","family":"Cowley","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julian C.","family":"Knight","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,10,7]]},"reference":[{"key":"18077_CR1","doi-asserted-by":"publisher","first-page":"244","DOI":"10.1016\/j.pharmthera.2007.10.001","volume":"117","author":"D Tracey","year":"2008","unstructured":"Tracey, D., Klareskog, L., Sasso, E. 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