{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,3]],"date-time":"2026-10-03T02:44:45Z","timestamp":1790995485450,"version":"4.1.0"},"reference-count":21,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2025,5,29]],"date-time":"2025-05-29T00:00:00Z","timestamp":1748476800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["ascpt.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clinical Translational Sci"],"published-print":{"date-parts":[[2025,6]]},"abstract":"<jats:title>ABSTRACT<\/jats:title><jats:p>Leukopenia is a common dose\u2010dependent side effect of azathioprine, often leading to drug discontinuation. Variants in <jats:italic>TPMT<\/jats:italic> and <jats:italic>NUDT15<\/jats:italic> are associated with azathioprine\u2010induced leukopenia but only explain 25% of cases. Thus, we aimed to identify novel genetic risk factors among TPMT and NUDT15 normal metabolizers through a genome\u2010wide association study (GWAS). Using BioVU, Vanderbilt's electronic health record linked to genetic data, we assembled a discovery cohort of new users of azathioprine. The analysis was conducted in 1184 new users of azathioprine who had no history of prior thiopurine use or an organ transplant. A replication cohort of 521 patients was derived from <jats:italic>All of Us<\/jats:italic>, an NIH\u2010funded project that links healthcare data and genetics. The GWAS was adjusted for sex, age, indication (inflammatory bowel disease, systemic lupus erythematosus, other autoimmune condition, or unknown), concurrent use of xanthine oxidase inhibitors (allopurinol or febuxostat) or immunosuppressants, prior <jats:italic>TPMT<\/jats:italic> or <jats:italic>NUDT15<\/jats:italic> testing, and 10 principal components of ancestry. In BioVU, 65% of patients were female with a median age of 44 [IQR: 30, 57] and 125 patients developed leukopenia. In <jats:italic>All of Us,<\/jats:italic> 69% were female with a median age of 51 [36, 61], and 44 patients developed leukopenia. An intronic variant in <jats:italic>PTPN2<\/jats:italic>, rs11664064, reached genome\u2010wide significance in BioVU (OR\u2009=\u20093.61; <jats:italic>p<\/jats:italic>\u2009=\u20091.96E\u20108) and replicated in <jats:italic>All of Us<\/jats:italic> (OR\u2009=\u20092.42, <jats:italic>p<\/jats:italic>\u2009=\u20090.039). Our finding suggests an association between rs11664064 in <jats:italic>PTPN2<\/jats:italic> and azathioprine\u2010induced leukopenia. <jats:italic>PTPN2<\/jats:italic> plays a role in immune cell development and differentiation, providing a plausible mechanism for this association.<\/jats:p>","DOI":"10.1111\/cts.70220","type":"journal-article","created":{"date-parts":[[2025,5,30]],"date-time":"2025-05-30T04:43:42Z","timestamp":1748580222000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["<scp><i>PTPN2<\/i><\/scp> and Leukopenia in Individuals With Normal <scp>TPMT<\/scp> and <scp>NUDT15<\/scp> Metabolizer Status Taking Azathioprine"],"prefix":"10.1111","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3143-5915","authenticated-orcid":false,"given":"Laura L.","family":"Daniel","sequence":"first","affiliation":[{"name":"Department of Medicine University of Miami  Coral Gables Florida 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