{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,19]],"date-time":"2026-01-19T08:28:05Z","timestamp":1768811285098,"version":"3.49.0"},"reference-count":35,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,10,16]],"date-time":"2023-10-16T00:00:00Z","timestamp":1697414400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Genet."],"abstract":"<jats:p><jats:bold>Introduction:<\/jats:bold> Specific alleles in human leukocyte antigens (HLAs) are associated with an increased risk of developing drug hypersensitivity reactions induced by abacavir, allopurinol, carbamazepine, oxcarbazepine, phenytoin, lamotrigine, or flucloxacillin. Transplant patients are genotyped for HLA as a routine practice to match a potential donor to a recipient. This study aims to investigate the feasibility and potential impact of repurposing these HLA genotype data from kidney transplant patients to prevent drug hypersensitivity reactions.<\/jats:p><jats:p><jats:bold>Methods:<\/jats:bold> A cohort of 1347 kidney transplant recipients has been genotyped in the Leiden University Medical Center (LUMC) using next-generation sequencing (NGS). The risk alleles <jats:italic>HLA-A*31:01, HLA-B*15:02, HLA-B*15:11, HLA-B*57:01,<\/jats:italic> and <jats:italic>HLA-B*58:01<\/jats:italic> were retrieved from the NGS data. Medical history, medication use, and allergic reactions were obtained from the patient\u2019s medical records. Carrier frequencies found were compared to a LUMC blood donor population.<\/jats:p><jats:p><jats:bold>Results:<\/jats:bold> A total of 13.1% of transplant cohort patients carried at least one of the five <jats:italic>HLA<\/jats:italic> risk alleles and therefore had an increased risk of drug-induced hypersensitivity for specific drugs. <jats:italic>HLA-A*31:01<\/jats:italic>, <jats:italic>HLA-B*15:02, HLA-B*57:01, and HLA-B*58:01<\/jats:italic> were found in carrier frequencies of 4.61%, 1.19%, 4.46%, and 3.35% respectively. No <jats:italic>HLA-B*15:11<\/jats:italic> carrier was found. In total nine <jats:italic>HLA-B*57:01<\/jats:italic> carriers received flucloxacillin and seven <jats:italic>HLA-B*58:01<\/jats:italic> carriers within our cohort received allopurinol.<\/jats:p><jats:p><jats:bold>Discussion:<\/jats:bold> Our study shows that repurposing HLA genotype data from transplantation patients for the assignment of HLA risk alleles associated with drug hypersensitivity is feasible. The use of these data by physicians while prescribing drugs or by the pharmacist when dispensing drugs holds the potential to prevent drug hypersensitivity reactions. The utility of this method was highlighted by 13.1% of the transplant cohort patients carrying an actionable HLA allele.<\/jats:p>","DOI":"10.3389\/fgene.2023.1289015","type":"journal-article","created":{"date-parts":[[2023,10,16]],"date-time":"2023-10-16T07:18:01Z","timestamp":1697440681000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":3,"title":["Repurposing HLA genotype data of renal transplant patients to prevent severe drug hypersensitivity reactions"],"prefix":"10.3389","volume":"14","author":[{"given":"Lisanne E. N.","family":"Manson","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sander J.","family":"Delwig","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jos J. M.","family":"Drabbels","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daan J.","family":"Touw","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aiko P. J.","family":"De Vries","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dave L.","family":"Roelen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Henk-Jan","family":"Guchelaar","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2023,10,16]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"806","DOI":"10.1038\/clpt.2011.58","article-title":"Case definition and phenotype standardization in drug-induced liver injury","volume":"89","author":"Aithal","year":"2011","journal-title":"Clin. Pharmacol. Ther."},{"key":"B2","doi-asserted-by":"publisher","first-page":"1203475420952422","DOI":"10.1177\/1203475420952422","article-title":"Human leukocyte antigen gene testing and carbamazepine-induced toxic epidermal necrolysis: a study of pediatric practice","volume":"25","author":"Asgarpour","year":"2021","journal-title":"J. Cutan. Med. Surg."},{"key":"B3","doi-asserted-by":"publisher","first-page":"437","DOI":"10.1007\/s40264-015-0281-0","article-title":"Epidemiology of adverse drug reactions in europe: a review of recent observational studies","volume":"38","author":"Bouvy","year":"2015","journal-title":"Drug Saf."},{"key":"B4","unstructured":"How many residents have a foreign country of origin?2023"},{"key":"B5","doi-asserted-by":"publisher","first-page":"426","DOI":"10.1089\/WOUND.2019.0977","article-title":"Toxic epidermal necrolysis and steven-johnson syndrome: a comprehensive review","volume":"9","author":"Charlton","year":"2020","journal-title":"Adv. wound care"},{"key":"B6","doi-asserted-by":"publisher","first-page":"1307","DOI":"10.1111\/EPI.12217","article-title":"HLA-B alleles associated with severe cutaneous reactions to antiepileptic drugs in Han Chinese","volume":"54","author":"Cheung","year":"2013","journal-title":"Epilepsia"},{"key":"B7","doi-asserted-by":"publisher","first-page":"816","DOI":"10.1038\/ng.379","article-title":"HLA-B5701 genotype is a major determinant of drug-induced liver injury due to flucloxacillin","volume":"41","author":"Daly","year":"2009","journal-title":"Nat. Genet."},{"key":"B8","unstructured":"Farmacogenetica | KNMP Kennisbank2023"},{"key":"B9","doi-asserted-by":"publisher","first-page":"895","DOI":"10.3390\/MEDICINA57090895","article-title":"Stevens-johnson syndrome and toxic epidermal necrolysis: a review of diagnosis and management","volume":"57","author":"Frantz","year":"2021","journal-title":"Med. Kaunas. Lith."},{"key":"B10","unstructured":"NGSgo\u00ae-MX11-3 - GenDx2023"},{"key":"B11","unstructured":"The Allele Frequency Net Database [AFND) 2020 update: gold-standard data classification, open access genotype data and new query tools, Nucleic Acid Research\n            Gonzalez-GalarzaF. F.\n            McCabeA.\n            SantosE. J. M. D.\n            JonesJ.\n            TakeshitaL.\n            Ortega-RiveraN. D.\n          2020"},{"key":"B12","doi-asserted-by":"publisher","first-page":"1","DOI":"10.18637\/JSS.V064.I03","article-title":"Exploring diallelic genetic markers: the hardyweinberg package","volume":"64","author":"Graffelman","year":"2015","journal-title":"J. Stat. Softw."},{"key":"B13","doi-asserted-by":"publisher","first-page":"1275","DOI":"10.1002\/HEP.29283","article-title":"Death and liver transplantation within 2 years of onset of drug-induced liver injury","volume":"66","author":"Hayashi","year":"2017","journal-title":"Hepatol. Baltim. Md.)"},{"key":"B14","doi-asserted-by":"publisher","first-page":"474","DOI":"10.1111\/tan.13535","article-title":"Next generation sequencing characterizes HLA diversity in a registry population from The Netherlands","volume":"93","author":"Hou","year":"2019","journal-title":"HLA"},{"key":"B15","doi-asserted-by":"publisher","first-page":"297","DOI":"10.1097\/01.fpc.0000199500.46842.4a","article-title":"Genetic susceptibility to carbamazepine-induced cutaneous adverse drug reactions","volume":"16","author":"Hung","year":"2006","journal-title":"Pharmacogenetics Genomics"},{"key":"B16","doi-asserted-by":"publisher","first-page":"95","DOI":"10.1620\/TJEM.233.95","article-title":"HLA-DR9 and DR14 are associated with the allopurinol-induced hypersensitivity in hematologic malignancy","volume":"233","author":"Jung","year":"2014","journal-title":"Tohoku J. Exp. Med."},{"key":"B17","doi-asserted-by":"publisher","first-page":"1071","DOI":"10.1111\/bjd.12501","article-title":"Drug reaction with eosinophilia and systemic symptoms (DRESS): an original multisystem adverse drug reaction Results from the prospective regiscar study","volume":"169","author":"Kardaun","year":"2013","journal-title":"Br. J. Dermatology"},{"key":"B18","doi-asserted-by":"publisher","first-page":"609","DOI":"10.1111\/j.1365-2133.2006.07704.x","article-title":"Variability in the clinical pattern of cutaneous side-effects of drugs with systemic symptoms: does a dress syndrome really exist? [20]","volume":"156","author":"Kardaun","year":"2007","journal-title":"Br. J. Dermatology"},{"key":"B19","unstructured":"Stevens-Johnson syndrome and toxic epidermal necrolysis: clinical manifestations; pathogenesis; and diagnosis\n            LeeH. L.\n          2013"},{"key":"B20","doi-asserted-by":"publisher","first-page":"99","DOI":"10.1097\/FPC.0B013E3282F3EF9C","article-title":"A European study of HLA-B in Stevens-Johnson syndrome and toxic epidermal necrolysis related to five high-risk drugs","volume":"18","author":"Lonjou","year":"2008","journal-title":"Pharmacogenetics genomics"},{"key":"B21","doi-asserted-by":"publisher","first-page":"338","DOI":"10.1053\/J.GASTRO.2011.04.001","article-title":"Susceptibility to amoxicillin-clavulanate-induced liver injury is influenced by multiple HLA class I and II alleles","volume":"141","author":"Lucena","year":"2011","journal-title":"Gastroenterology"},{"key":"B22","doi-asserted-by":"publisher","first-page":"568","DOI":"10.1056\/nejmoa0706135","article-title":"HLA-B*5701 screening for hypersensitivity to abacavir","volume":"358","author":"Mallal","year":"2008","journal-title":"N. Engl. J. Med."},{"key":"B23","doi-asserted-by":"publisher","first-page":"1233","DOI":"10.1002\/ACR.21671","article-title":"Increased frequency of DRB1*11:01 in anti-hydroxymethylglutaryl-coenzyme A reductase-associated autoimmune myopathy","volume":"64","author":"Mammen","year":"2012","journal-title":"Arthritis care & Res."},{"key":"B24","doi-asserted-by":"publisher","first-page":"567048","DOI":"10.3389\/fphar.2020.567048","article-title":"Diagnostic test criteria for HLA genotyping to prevent drug hypersensitivity reactions: a systematic review of actionable HLA recommendations in CPIC and DPWG guidelines","volume":"11","author":"Manson","year":"2020","journal-title":"Front. Pharmacol."},{"key":"B25","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1186\/s12981-019-0217-3","article-title":"HLA-B*57:01 screening and hypersensitivity reaction to abacavir between 1999 and 2016 in the OPERA\u00ae observational database: a cohort study","volume":"16","author":"Mounzer","year":"2019","journal-title":"AIDS Res. Ther."},{"key":"B26","doi-asserted-by":"publisher","first-page":"1271","DOI":"10.1016\/J.JAIP.2018.12.012","article-title":"Efficacy of the HLA-B\u221758:01 screening test in preventing allopurinol-induced severe cutaneous adverse reactions in patients with chronic renal insufficiency-A prospective study","volume":"7","author":"Park","year":"2019","journal-title":"J. allergy Clin. Immunol. Pract."},{"key":"B27","doi-asserted-by":"publisher","first-page":"1197","DOI":"10.1038\/JID.2012.510","article-title":"Comprehensive survival analysis of a cohort of patients with Stevens-Johnson syndrome and toxic epidermal necrolysis","volume":"133","author":"Sekula","year":"2013","journal-title":"J. investigative dermatology"},{"key":"B28","doi-asserted-by":"publisher","first-page":"662","DOI":"10.1038\/CLPT.2011.34","article-title":"Pharmacogenetics: from bench to byte\u2014 an update of guidelines","volume":"89","author":"Swen","year":"2011","journal-title":"Clin. Pharmacol. Ther."},{"key":"B29","doi-asserted-by":"publisher","first-page":"347","DOI":"10.1016\/S0140-6736(22)01841-4","article-title":"A 12-gene pharmacogenetic panel to prevent adverse drug reactions: an open-label, multicentre, controlled, cluster-randomised crossover implementation study","volume":"401","author":"Swen","year":"2023","journal-title":"Lancet"},{"key":"B30","doi-asserted-by":"publisher","first-page":"781","DOI":"10.1038\/SJ.CLPT.6100507","article-title":"Pharmacogenetics: from bench to byte","volume":"83","author":"Swen","year":"2008","journal-title":"Clin. Pharmacol. Ther."},{"key":"B31","doi-asserted-by":"publisher","first-page":"617","DOI":"10.1002\/cpt.1665","article-title":"Repurposing of diagnostic whole exome sequencing data of 1,583 individuals for clinical pharmacogenetics","volume":"107","author":"van der Lee","year":"2020","journal-title":"Clin. Pharmacol. Ther."},{"key":"B32","doi-asserted-by":"publisher","first-page":"866","DOI":"10.1002\/CPT.1489","article-title":"Development of the PGx-passport: a panel of actionable germline genetic variants for pre-emptive pharmacogenetic testing","volume":"106","author":"van der Wouden","year":"2019","journal-title":"Clin. Pharmacol. Ther."},{"key":"B33","unstructured":"International drug monitoring: the role of national centres. Report of a WHO meeting1972"},{"key":"B34","doi-asserted-by":"publisher","first-page":"81870","DOI":"10.18632\/oncotarget.13250","article-title":"Impact of HLA-B*58: 01 allele and allopurinol-induced cutaneous adverse drug reactions: evidence from 21 pharmacogenetic studies","volume":"7","author":"Wu","year":"2016","journal-title":"Oncotarget"},{"key":"B35","doi-asserted-by":"publisher","first-page":"757","DOI":"10.1038\/clpt.2012.189","article-title":"HLA genotype and carbamazepine-induced cutaneous adverse drug reactions: a systematic review","volume":"92","author":"Yip","year":"2012","journal-title":"Clin. Pharmacol. Ther."}],"container-title":["Frontiers in Genetics"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fgene.2023.1289015\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,10,16]],"date-time":"2023-10-16T07:18:05Z","timestamp":1697440685000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fgene.2023.1289015\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,10,16]]},"references-count":35,"alternative-id":["10.3389\/fgene.2023.1289015"],"URL":"https:\/\/doi.org\/10.3389\/fgene.2023.1289015","relation":{},"ISSN":["1664-8021"],"issn-type":[{"value":"1664-8021","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,10,16]]},"article-number":"1289015"}}