{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,1,16]],"date-time":"2026-01-16T13:06:33Z","timestamp":1768568793798,"version":"3.49.0"},"posted":{"date-parts":[[2025,5,25]]},"group-title":"Allergy and Immunology","reference-count":15,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,5,25]],"date-time":"2025-05-25T00:00:00Z","timestamp":1748131200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.medrxiv.org\/about\/FAQ#license"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,5,25]]},"abstract":"ABSTRACT<\/jats:title>\n \n Importance<\/jats:title>\n Carriage of HLA-B*58:01 has been shown to have a strong association with the development of allopurinol-induced Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS\/TEN) and drug reaction and eosinophilia and systemic symptoms (DRESS) in many populations globally; however, there is a critical need to determine if this is generalizable to varying populations including those in the United States (US).<\/jats:p>\n <\/jats:sec>\n \n Objective<\/jats:title>\n To perform HLA class I and II association studies in a cohort of US patients diagnosed with allopurinol-induced SJS\/TEN or DRESS compared to allopurinol tolerant and population controls.<\/jats:p>\n <\/jats:sec>\n \n Design, Setting, and Participants<\/jats:title>\n We enrolled consenting individuals who had specialist adjudicated allopurinol-induced SJS\/TEN or DRESS (collectively allopurinol-SCAR). HLA carriage in these cases was compared to allopurinol tolerant and population controls identified through Vanderbilt University Medical Center (VUMC) BioVU, a biobank which includes 94,489 individuals with imputed human leukocyte antigen (HLA) class I and II typing from genotyping array data.<\/jats:p>\n <\/jats:sec>\n \n Main Outcomes and Measures<\/jats:title>\n \n We performed HLA class I and II conditional logistic regression case-control analyses between allopurinol-SCAR cases and both population controls and allopurinol tolerant controls matched on age, sex, and self-identified race. We reported odds ratio (OR) and 95% confidence interval (CI) with Bonferroni corrected\n P<\/jats:italic>\n (\n Pc<\/jats:italic>\n ) <.05.\n <\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n The conditional logistic regression analyses included allopurinol-SCAR cases (n=16) and 10:1 matched allopurinol tolerant controls (n=160). We found two HLA class I alleles independently associated with increased risk of allopurinol-induced SCAR: HLA-B*58:01 (OR 28 [95% CI, 8.6 \u2013 100.6]) and HLA-A*34:02 (OR 20.6 [95% CI, 3.3 \u2013 131.1]). We did not identify any HLA class II alleles meeting the Pc level of significance.<\/jats:p>\n <\/jats:sec>\n \n Conclusions and Relevance<\/jats:title>\n We found HLA-B*58:01 to be strongly associated with allopurinol-induced SCAR, generalizing findings from previous studies. Additionally, we found HLA-A*34:02 to be a second independent genetic risk factor for allopurinol-SCAR. These findings underscore the need to conduct specific population-based studies that both reproduce known and uncover novel HLA associations in order to reduce harm through contributions to screening, risk stratification, and diagnosis.<\/jats:p>\n <\/jats:sec>\n \n KEY POINTS<\/jats:title>\n \n Question<\/jats:title>\n Is the association between HLA-B*58:01 and allopurinol-SCAR generalizable to admixed populations in the US or are additional HLA associations involved?<\/jats:p>\n <\/jats:sec>\n \n Findings<\/jats:title>\n In this HLA association study with 16 patients of primarily self-identified Black race of adjudicated allopurinol-induced SJS\/TEN or DRESS, we demonstrate a strong association with the established risk allele, HLA-B*58:01, and, for the first time, identified HLA-A*34:02 as an additional independent risk factor.<\/jats:p>\n <\/jats:sec>\n \n Meaning<\/jats:title>\n HLA-B*58:01 is absent in more than one-third of our US cohort of allopurinol-SCAR cases suggesting that more comprehensive screening and diagnostic approaches are necessary to prevent additional cases in genetically heterogenous populations.<\/jats:p>\n <\/jats:sec>\n <\/jats:sec>","DOI":"10.1101\/2025.05.23.25328236","type":"posted-content","created":{"date-parts":[[2025,5,25]],"date-time":"2025-05-25T13:30:16Z","timestamp":1748179816000},"source":"Crossref","is-referenced-by-count":1,"title":["HLA-B*58:01 is an Incomplete Predictor of Allopurinol-Induced Severe Cutaneous Adverse Reactions"],"prefix":"10.64898","author":[{"given":"Chelsea N.","family":"Campbell","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Matthew S.","family":"Krantz","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alexis","family":"Yu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elizabeth J.","family":"Phillips","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"name":"the SJS Survivor Study","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2025052709101234000_2025.05.23.25328236v1.1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0409500102"},{"key":"2025052709101234000_2025.05.23.25328236v1.2","doi-asserted-by":"publisher","DOI":"10.1097\/FPC.0b013e3282f3ef9c"},{"key":"2025052709101234000_2025.05.23.25328236v1.3","doi-asserted-by":"publisher","DOI":"10.1111\/bjd.12389"},{"key":"2025052709101234000_2025.05.23.25328236v1.4","doi-asserted-by":"publisher","DOI":"10.2165\/00003088-198611050-00001"},{"key":"2025052709101234000_2025.05.23.25328236v1.5","doi-asserted-by":"publisher","DOI":"10.1016\/j.semarthrit.2016.03.014"},{"key":"2025052709101234000_2025.05.23.25328236v1.6","doi-asserted-by":"publisher","DOI":"10.1053\/j.ajkd.2018.06.021"},{"key":"2025052709101234000_2025.05.23.25328236v1.7","doi-asserted-by":"publisher","DOI":"10.1038\/clpt.2008.89"},{"key":"2025052709101234000_2025.05.23.25328236v1.8","doi-asserted-by":"publisher","DOI":"10.18637\/jss.v042.i08"},{"key":"2025052709101234000_2025.05.23.25328236v1.9","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0064683"},{"key":"2025052709101234000_2025.05.23.25328236v1.10","doi-asserted-by":"publisher","DOI":"10.1016\/j.humimm.2018.09.008"},{"key":"2025052709101234000_2025.05.23.25328236v1.11","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pcbi.1009131"},{"key":"2025052709101234000_2025.05.23.25328236v1.12","doi-asserted-by":"publisher","DOI":"10.1111\/j.1469-1809.1955.tb01285.x"},{"key":"2025052709101234000_2025.05.23.25328236v1.13","unstructured":"Sjoberg D , Baillie M , Fruechtenicht C , Haesendonckx S , Treis T (2025). ggsurvfit: Flexible Time-to-Event Figures. 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