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HLA-B*5701 genotype is a major determinant of drug-induced liver injury due to flucloxacillin

Abstract

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.

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Figure 1: Flucloxacillin DILI genome-wide association result.
Figure 2: Quantile-quantile plot of χ2 statistics in case-control study.

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Acknowledgements

The DILIGEN sample collection and MHC genotyping was funded by the UK Department of Health (Pharmacogenetics Initiative ref PHGX10A). The GWA study and additional case collection during 2008 was funded by the International Serious Adverse Events Consortium with support from Abbott, Daiichi-Sankyo, GlaxoSmithKline, Johnson & Johnson, Novartis, Pfizer, F. Hoffmann-La Roche, Sanofi-Aventis, Takeda, Wellcome Trust and Wyeth. We extend special thanks to the research committees of British Association for Study of the Liver and British Society for Gastroenterology for help with publicizing the study, to the UK Medicines and Healthcare Products Regulatory Agency for enabling access to a yellow card case and to the subjects for their participation.

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A.K.D., P.T.D., B.K.P., M.P., G.P.A. and C.P.D. participated in the conception, design and coordination of the DILIGEN study and in writing the paper; P.B., Y.S., I.P., A.F., M.R.N. and H.J.C. analyzed the data and participated in writing the paper; M.J.D., D.B.G., S.J. and the International Serious Adverse Events Consortium advised on the GWA study and participated in writing the paper; J.G. performed DNA extraction and genotyping; W.B., J.F.D. and the DILIGEN study members recruited study subjects and provided clinical data.

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Correspondence to Ann K Daly.

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Competing interests

M.R.N. is a full-time employee of GlaxoSmithKline, S.J. is a full-time employee of Pfizer Inc., D.B.G. is a paid consultant for GlaxoSmithKline and the Serious Adverse Events Consortium.

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A full list of members is provided in the Supplementary Note.

A full list of members is provided in the Supplementary Note.

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Supplementary Note, Supplementary Results, Supplementary Tables 1–11 and Supplementary Figures 1–5 (PDF 2344 kb)

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Daly, A., Donaldson, P., Bhatnagar, P. et al. HLA-B*5701 genotype is a major determinant of drug-induced liver injury due to flucloxacillin. Nat Genet 41, 816–819 (2009). https://doi.org/10.1038/ng.379

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