Original ResearchBasic and Translational-LiverSusceptibility to Amoxicillin-Clavulanate-Induced Liver Injury Is Influenced by Multiple HLA Class I and II Alleles
Section snippets
Case Recruitment
Cases (n = 211) were recruited in 4 separate studies (DILIGEN,16 Spanish DILI Registry,6 Drug-induced liver injury network [DILIN],7 and EUDRAGENE17) that used similar inclusion criteria. All participants provided written informed consent, and each study had been approved by the appropriate ethical review boards.
Clinical Characteristics of the Cases
Clinical details of the 201 cases included in this study are summarized in Table 1. As in previous studies of AC-DILI, there were more male than female cases. The average age at onset was 61 ± 14 years. Four cases underwent liver transplantation. Most cases (70%) were characterized as cholestatic or mixed at presentation, and 88% had bilirubin levels >2.4 mg/dL. Most causality scores (93%) suggested that DILI was either probably or highly likely because of AC. There were some significant
Discussion
This study was accomplished through an international cooperation to assemble a considerably larger and more diverse AC-DILI patient collection than previous published studies on the subject.11, 12, 13 This resulted in the most powerful and comprehensive investigation into genetic risk factors for AC-DILI and the largest GWA for any rare serious adverse event conducted to date. We confirmed the previous associations of HLA-DRB1*1501 and DQB1*0602 with DILI susceptibility, and our larger sample
Acknowledgments
Contributors to sample collection via Spanish DILI network, EUDRAGENE, DILIN, and DILIGEN are listed in the Appendix.
Drs Lucena, Molokhia, Shen, and Daly contributed equally to this manuscript.
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Conflicts of interest The authors disclose the following: Dr Fontana acted as a consultant to GlaxoSmithKline. Dr Nelson is an employee of GlaxoSmith Kline. The remaining authors disclose no conflicts.
Funding The genome-wide association study and HLA genotyping was funded by the International Serious Adverse Events Consortium with support from Abbott, Daiichi-Sankyo, GlaxoSmithKline, Johnson & Johnson, Novartis, Pfizer, Roche, Sanofi-Aventis, Takeda, Wellcome Trust, and Wyeth. The DILIGEN sample collection was partly funded by the UK Department of Health (ref. PHGX10A) and by UK NIHR funding to the Nottingham Digestive Diseases Centre. The DILIN network is structured as a U01 cooperative agreement with funds provided by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) under grants 2U01-DK065176-06 (Duke), 2U01-DK065201-06 (UNC), 2U01-DK065184-06 (Michigan), 2U01-DK065211-06 (Indiana), 5U01DK065193-04 (UConn), 5U01-DK065238-08 (UCSF/CPMC). Additional funding is provided by CTSA grants UL1 RR025761 (Indiana), UL1 RR025747 (UNC), and UL1 UL1 RR024986 (UMich). The EUDRAGENE collaboration has received support from the EC 5th Framework program (QLRI-CT-2002-02757) and the SAEC. The UK NIHR postdoctoral award funded Mariam Molokhia. The Spanish DILI Registry is partly funded by the Spanish Medicine Agency and has received support from SAEC and Boehringer-Ingelheim, Barcelona, Spain. CIBERehd and RETIC are funded by Instituto de Salud Carlos III. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.