Letter abstract
Nature Genetics 41, 816 - 819 (2009)
Published online: 31 May 2009 | doi:10.1038/ng.379
HLA-B*5701 genotype is a major determinant of drug-induced liver injury due to flucloxacillin
Ann K Daly1, Peter T Donaldson1, Pallav Bhatnagar1, Yufeng Shen2, Itsik Pe'er2, Aris Floratos2, Mark J Daly3, David B Goldstein4, Sally John5, Matthew R Nelson6, Julia Graham1, B Kevin Park7, John F Dillon8, William Bernal9, Heather J Cordell1, Munir Pirmohamed7, Guruprasad P Aithal10,11, Christopher P Day1,11, for the DILIGEN study12 & International SAE Consortium12
Drug-induced liver injury (DILI) is an important cause of serious liver disease. The antimicrobial agent flucloxacillin is a common cause of DILI, but the genetic basis for susceptibility remains unclear. We conducted a genome-wide association (GWA) study using 866,399 markers in 51 cases of flucloxacillin DILI and 282 controls matched for sex and ancestry. The GWA showed an association peak in the major histocompatibility complex (MHC) region with the strongest association (P = 8.7 
10-33) seen for rs2395029[G], a marker in complete linkage disequilibrium (LD) with HLA-B*5701. Further MHC genotyping, which included 64 flucloxacillin-tolerant controls, confirmed the association with HLA-B*5701 (OR = 80.6, P = 9.0 10-19). The association was replicated in a second cohort of 23 cases. In HLA-B*5701 carrier cases, rs10937275 in ST6GAL1 on chromosome 3 also showed genome-wide significance (OR = 4.1, P = 1.4 10-8). These findings provide new insights into the mechanism of flucloxacillin DILI and have the potential to substantially improve diagnosis of this serious disease.
- Institute of Cellular Medicine and Institute of Human Genetics, Newcastle University, Newcastle upon Tyne, UK.
- Columbia University, New York, New York, USA.
- Harvard Medical School, Boston, Massachusetts, USA.
- Duke University, Durham, North Carolina, USA.
- Pfizer Inc., New London, Connecticut, USA.
- GlaxoSmithKline, Research Triangle Park, North Carolina, USA.
- Department of Pharmacology and Therapeutics, University of Liverpool, Liverpool, UK.
- Ninewells Hospital and Medical School, Dundee, UK.
- Kings College Hospital, London, UK.
- Nottingham Digestive Diseases Centre: Biomedical Research Unit, Nottingham, UK.
- These authors contributed equally to this work.
- A full list of members is provided in the Supplementary Note online.
Correspondence to: Ann K Daly1 e-mail: a.k.daly@ncl.ac.uk
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