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The DOI matches its Crossref record; 6 of the 6 references it cites were found in a registry or an index.

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

for the DILIGEN study, Daly, Ann K, International SAE Consortium, Donaldson, Peter T, Bhatnagar, Pallav, Shen, Yufeng, Pe'er, Itsik, Floratos, Aris, Daly, Mark J, Goldstein, David B, John, Sally, Nelson, Matthew R, Graham, Julia, Park, B Kevin, Dillon, John F, Bernal, William, Cordell, Heather J, Pirmohamed, Munir, Aithal, Guruprasad P, Day, Christopher P·2009·Nature Genetics
DOI 10.1038/ng.379
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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 x 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 x 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 x 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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Crossref · 10.1038/ng.379

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Research works printed but not linked: 31

  1. Mann, R. & Andrews, E. (eds.). Pharmacovigilance (John Wiley and Sons, Chichester, 2006). · DOI
  2. Sgro, C. et al. Incidence of drug-induced hepatic injuries: a French population-based study. Hepatology 36, 451–455 (2002). · DOI · Paper page
  3. Ostapowicz, G. et al. Results of a prospective study of acute liver failure at 17 tertiary care centers in the United States. Ann. Intern. Med. 137, 947–954 (2002). · DOI · Paper page
  4. Olsson, R. et al. Liver damage fron flucloxacillin, cloxacillin and dicloxacillin. J. Hepatol. 15, 154–161 (1992). · DOI
  5. Fairley, C.K., McNeil, J. & Desmond, P. Risk factors for development of flucloxacillin associated jaundice. Br. Med. J. 306, 233–235 (1993). · DOI
  6. Russmann, S., Kaye, J.A., Jick, S.S. & Jick, H. Risk of cholestatic liver disease associated with flucloxacillin and flucloxacillin prescribing habits in the UK: cohort study using data from the UK General Practice Research Database. Br. J. Clin. Pharmacol. 60, 76–82 (2005). · DOI · Paper page
  7. Hautekeete, M.L. et al. HLA association of amoxicillin-clavulanate-induced hepatitis. Gastroenterology 117, 1181–1186 (1999). · DOI · Paper page
  8. O'Donohue, J. et al. Co-amoxiclav jaundice: clinical and histological features and HLA class II association. Gut 47, 717–720 (2000). · DOI · Paper page
  9. Kindmark, A. et al. Genome-wide pharmacogenetic investigation of a hepatic adverse event without clinical signs of immunopathology suggests an underlying immune pathogenesis. Pharmacogenomics J. 8, 186–195 (2008). · DOI
  10. Lakehal, F. et al. Indirect cytotoxicity of flucloxacillin toward human biliary epithelium via metabolite formation in hepatocytes. Chem. Res. Toxicol. 14, 694–701 (2001). · DOI
  11. Maria, V.A. & Victorino, R.M. Diagnostic value of specific T cell reactivity to drugs in 95 cases of drug induced liver injury. Gut 41, 534–540 (1997). · DOI
  12. Danan, G. & Benichou, C. Causality assessment of adverse reactions to drugs–I. A novel method based on the conclusions of international consensus meetings: application to drug-induced liver injuries. J. Clin. Epidemiol. 46, 1323–1330 (1993). · DOI · Paper page
  13. Colombo, S. et al. The HCP5 single-nucleotide polymorphism: a simple screening tool for prediction of hypersensitivity reaction to abacavir. J. Infect. Dis. 198, 864–867 (2008). · DOI
  14. Pachkoria, K. et al. Analysis of IL-10, IL-4 and TNF-α polymorphisms in drug-induced liver injury (DILI) and its outcome. J. Hepatol. 49, 107–114 (2008). · DOI
  15. Aithal, G.P. et al. Hepatic adducts, circulating antibodies, and cytokine polymorphisms in patients with diclofenac hepatotoxicity. Hepatology 39, 1430–1440 (2004). · DOI
  16. Donaldson, P.T. Genetics of liver disease: immunogenetics and disease pathogenesis. Gut 53, 599–608 (2004). · DOI
  17. Ahmad, T. et al. Haplotype-specific linkage disequilibrium patterns define the genetic topography of the human MHC. Hum. Mol. Genet. 12, 647–656 (2003). · DOI
  18. Browner, W.S. & Newman, T.B. Sample size and power based on the population attributable fraction. Am. J. Public Health 79, 1289–1294 (1989). · DOI
  19. Bast, B.J. et al. The HB-6, CDw75, and CD76 differentiation antigens are unique cell-surface carbohydrate determinants generated by the β-galactoside α 2,6-sialyltransferase. J. Cell Biol. 116, 423–435 (1992). · DOI
  20. Hetherington, S. et al. Hypersensitivity reactions during therapy with the nucleoside reverse transcriptase inhibitor abacavir. Clin. Ther. 23, 1603–1614 (2001). · DOI · Paper page
  21. Chessman, D. et al. Human leukocyte antigen class I-restricted activation of CD8+ T cells provides the immunogenetic basis of a systemic drug hypersensitivity. Immunity 28, 822–832 (2008). · DOI · Paper page
  22. Fellay, J. et al. A whole-genome association study of major determinants for host control of HIV-1. Science 317, 944–947 (2007). · DOI · Paper page
  23. Kaplan, H.A., Woloski, B.M., Hellman, M. & Jamieson, J.C. Studies on the effect of inflammation on rat liver and serum sialyltransferase. J. Biol. Chem. 258, 11505–11509 (1983). · DOI
  24. Nasirikenari, M., Segal, B.H., Ostberg, J.R., Urbasic, A. & Lau, J.T. Altered granulopoietic profile and exaggerated acute neutrophilic inflammation in mice with targeted deficiency in the sialyltransferase ST6Gal I. Blood 108, 3397–3405 (2006). · DOI
  25. Sutherland, R., Croydon, E.A. & Rolinson, G.N. Flucloxacillin, a new isoxazolyl penicillin, compared with oxacillin, cloxacillin, and dicloxacillin. BMJ 4, 455–460 (1970). · DOI
  26. Willer, C.J. et al. Six new loci associated with body mass index highlight a neuronal influence on body weight regulation. Nat. Genet. 41, 25–34 (2009). · DOI · Paper page
  27. Nelson, M.R. et al. Genome-wide approaches to identify pharmacogenetic contributions to adverse drug reactions. Pharmacogenomics J. 9, 23–33 (2008). · DOI
  28. Grove, J., Daly, A.K., Bassendine, M.F. & Day, C.P. Association of a tumor necrosis factor promoter polymorphism with susceptibility to alcoholic steatohepatitis. Hepatology 26, 143–146 (1997). · DOI · Paper page
  29. Daly, A.K., King, B.P. & Leathart, J.B. Genotyping for cytochrome P450 polymorphisms. Methods Mol. Biol. 320, 193–207 (2006).
  30. Svejgaard, A. & Ryder, L.P. HLA and disease associations: detecting the strongest association. Tissue Antigens 43, 18–27 (1994). · DOI
  31. Dudbridge, F. Likelihood-based association analysis for nuclear families and unrelated subjects with missing genotype data. Hum. Hered. 66, 87–98 (2008). · DOI · Paper page

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Metadata

Authors
study, F. T. D., Daly, A. K., International SAE Consortium, Donaldson, P. T., Bhatnagar, P., Shen, Y., Pe'er, I., Floratos, A., Daly, M. J., Goldstein, D. B., John, S., Nelson, M. R., Graham, J., Park, B. K., Dillon, J. F., Bernal, W., Cordell, H. J., Pirmohamed, M., Aithal, G. P., & Day, C. P.
Venue
Nature Genetics
Publisher
Springer Science and Business Media LLC
Published
2009-05-31
Volume
41
Issue
7
Pages
816-819
ISSN
  • 1061-4036
  • 1546-1718
DOI
10.1038/ng.379
Cited by
944
References
6
Language
en
Licence
www.springer.com/tdm (tdm)

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CoChat. (2026). Citation check: HLA-B*5701 genotype is a major determinant of drug-induced liver injury due to flucloxacillin. https://app.cochat.ai/papers/10.1038/ng.379
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study, F. T. D., Daly, A. K., International SAE Consortium, Donaldson, P. T., Bhatnagar, P., Shen, Y., Pe'er, I., Floratos, A., Daly, M. J., Goldstein, D. B., John, S., Nelson, M. R., Graham, J., Park, B. K., Dillon, J. F., Bernal, W., Cordell, H. J., Pirmohamed, M., Aithal, G. P., & Day, C. P. (2009). HLA-B*5701 genotype is a major determinant of drug-induced liver injury due to flucloxacillin. Nature Genetics. https://doi.org/10.1038/ng.379

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