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Therapeutics"],"published-print":{"date-parts":[[2019,7]]},"abstract":"\n Some patients prescribed flucloxacillin (~\u00a00.01%) develop drug\u2010induced liver injury (\n DILI<\/jats:styled-content>\n ).\n \n HLA<\/jats:styled-content>\n \u2010B*57:01\n <\/jats:italic>\n is an established genetic risk factor for flucloxacillin\n DILI<\/jats:styled-content>\n . To consolidate this finding, identify additional genetic factors, and assess relevance of risk factors for flucloxacillin\n DILI<\/jats:styled-content>\n in relation to\n DILI<\/jats:styled-content>\n due to other penicillins, we performed a genomewide association study involving 197 flucloxacillin\n DILI<\/jats:styled-content>\n cases and 6,835 controls. We imputed single\u2010nucleotide polymorphism and human leukocyte antigen (HLA) genotypes.\n \n HLA<\/jats:styled-content>\n \u2010B*57:01\n <\/jats:italic>\n was the major risk factor (allelic odds ratio (\n OR<\/jats:styled-content>\n )\u00a0=\u00a036.62;\n P<\/jats:italic>\n \u00a0=\u00a02.67\u00a0\u00d7\u00a010\n \u221297<\/jats:sup>\n ).\n \n HLA<\/jats:styled-content>\n \u2010B*57:03\n <\/jats:italic>\n also showed an association (\n OR<\/jats:styled-content>\n \u00a0=\u00a079.21;\n P<\/jats:italic>\n \u00a0=\u00a01.2\u00a0\u00d7\u00a010\n \u22126<\/jats:sup>\n ). Within the\n HLA<\/jats:styled-content>\n \u2010B protein sequence, imputation showed valine\n 97<\/jats:sup>\n , common to\n HLA<\/jats:styled-content>\n \u2010B*57:01 and\n HLA<\/jats:styled-content>\n \u2010B*57:03, had the largest effect (\n OR<\/jats:styled-content>\n \u00a0=\u00a038.1;\n P<\/jats:italic>\n \u00a0=\u00a09.7\u00a0\u00d7\u00a010\n \u221297<\/jats:sup>\n ). We found no\n \n HLA<\/jats:styled-content>\n \u2010B*57\n <\/jats:italic>\n association with\n DILI<\/jats:styled-content>\n due to other isoxazolyl penicillins (\n n<\/jats:italic>\n \u00a0=\u00a06) or amoxicillin (\n n<\/jats:italic>\n \u00a0=\u00a015) and no significant non\u2010\n HLA<\/jats:styled-content>\n signals for any penicillin\u2010related\n DILI<\/jats:styled-content>\n .\n <\/jats:p>","DOI":"10.1002\/cpt.1375","type":"journal-article","created":{"date-parts":[[2019,1,20]],"date-time":"2019-01-20T00:48:02Z","timestamp":1547945282000},"page":"245-253","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":90,"title":["Drug\u2010Induced Liver Injury due to Flucloxacillin: Relevance of Multiple Human Leukocyte Antigen Alleles"],"prefix":"10.1111","volume":"106","author":[{"given":"Paola","family":"Nicoletti","sequence":"first","affiliation":[{"name":"Department of Genetics and Genomic Sciences Icahn School of Medicine at Mount Sinai New York New York USA"},{"name":"Sema4, a Mount Sinai Venture Stamford Connecticut USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guruprasad P.","family":"Aithal","sequence":"additional","affiliation":[{"name":"National Institute for Health Research (NIHR) Nottingham Biomedical Research Centre Nottingham University Hospital NHS Trust and University of Nottingham Nottingham UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas C.","family":"Chamberlain","sequence":"additional","affiliation":[{"name":"Institute of Cellular Medicine Newcastle University Newcastle upon Tyne UK"},{"name":"University of British Columbia Vancouver British Columbia Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sally","family":"Coulthard","sequence":"additional","affiliation":[{"name":"Institute of Cellular Medicine Newcastle University Newcastle upon Tyne UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohammad","family":"Alshabeeb","sequence":"additional","affiliation":[{"name":"Institute of Cellular Medicine Newcastle University Newcastle upon Tyne UK"},{"name":"Developmental Medicine Department King Abdullah International Medical Research Center Riyadh Kingdom of Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jane I.","family":"Grove","sequence":"additional","affiliation":[{"name":"National Institute for Health Research (NIHR) Nottingham Biomedical Research Centre Nottingham University Hospital NHS Trust and University of Nottingham Nottingham UK"},{"name":"Nottingham Digestive Diseases Centre School of Medicine University of Nottingham Nottingham UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raul J.","family":"Andrade","sequence":"additional","affiliation":[{"name":"UGC Digestivo y Servicio de Farmacolog\u00eda Cl\u00ednica Instituto de Investigaci\u00f3n Biom\u00e9dica de M\u00e1laga (IBIMA) Hospital Universitario Virgen de la Victoria Universidad de M\u00e1laga M\u00e1laga Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades Hep\u00e1ticas y Digestivas (CIBERehd) Madrid Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Einar","family":"Bjornsson","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology and Hepatology Department of Internal Medicine The National University Hospital of Iceland Reykjavik Iceland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John F.","family":"Dillon","sequence":"additional","affiliation":[{"name":"Medical Research Institute University of Dundee Ninewells Hospital Dundee UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Par","family":"Hallberg","sequence":"additional","affiliation":[{"name":"Department of Medical Sciences and Science for Life Laboratory Uppsala University Uppsala Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M. 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