for the International Drug-induced Liver Injury consortium (idilic) and DILIN

Transcription

1 Multiple HLA B*57 alleles, sharing the amin acid residue Valine 97, are assciated with drug-induced liver injury (DILI) due t fluclxacillin in a Eurpean ppulatin. Guruprasad P. Aithal, Pala Nicletti, Thmas C. Chamberlain, Sally Culthard, Mhammad Al-Shabeeb, Raul Andrade, Einar Bjrnssn, Jhn F. Dilln, Par Hallberg, M. Isabel Lucena, Anke H. Maitland-van der Zee, Jennifer H. Martin, Mariam Mlkhia, Munir Pirmhamed, Mia Wadelius, Aris Flrats, Yufeng Shen, Paul B. Watkins, Matthew R. Nelsn and Ann K. Daly 1

2 Natinal Institute fr Health Research (NIHR) Nttingham Bimedical Research Centre, Nttingham University Hspital NHS Trust and University f Nttingham, Nttingham, UK Department f Genetics and Genmic Sciences, Icahn Schl f Medicine at Munt Sinai, New Yrk, USA Institute f Cellular Medicine, Newcastle University, Newcastle upn Tyne, UK UGC Digestiv, Institut de Investigación Bimédica de Málaga (IBIMA), Hspital Universitari Virgen de la Victria, Universidad de Málaga, Málaga, Spain; Centr de Investigación Bimédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd); Divisin f Gastrenterlgy and Hepatlgy, Department f Internal Medicine, The Natinal University Hspital f Iceland, Reykjavik, Iceland Medical Research Institute, University f Dundee,Ninewells Hspital, Dundee, UK; Department f Medical Sciences and Science fr Life Labratry, Uppsala University, Uppsala, Sweden; Divisin f Pharmacepidemilgy and Clinical Pharmaclgy, Utrecht University, Utrecht, Netherlands; Schl f Medicine and Public Health, University f Newcastle, New Suth Wales, Australia; Department f Primary Care and Public Health Sciences, King's Cllege, Lndn, UK; Department f Mlecular and Clinical Pharmaclgy, University f Liverpl, Liverpl, UK; The Herbert Irving Cmprehensive Cancer Center, Clumbia University, New Yrk, USA Department f Bimedical Infrmatics, Clumbia University, New Yrk, USA UNC Eshelman Schl f Pharmacy, Chapel Hill, NC, USA Target Sciences, GSK, King f Prussia, PA, USA fr the Internatinal Drug-induced Liver Injury cnsrtium (idilic) and DILIN 2017 AMERICAN ASSOCIATION FOR THE STUDY OF LIVER DISEASES 2

3 Fluclxacillin and Drug-induced Liver Injury (DILI) Beta-lactamase resistant penicillin with isxazlyl ring; effective in the treatment f staphylcccal infectins Used widely especially in UK, Australia and Sweden DILI in per 100,000 peple Presentatin within 45 days f 1 st expsure 2 nd mst imprtant cause f DILI in the UK Rash and fever described Fatality and vanishing bile duct syndrme Li et al. Br J Clin Pharmacl 2009; 68:2:

4 Genme-Wide Assciatin Study (GWAS): Fluclxacillin DILI Strngest signal with SNP in HCP5 gene which tags HLA-B*57:01! Daly et al. Nature Genetics 2009; 41:

5 Genetic studies n DILI susceptibility DILIGEN (UK-based) DILI due t c-amxiclav, fluclxacillin, anti-tb agents, diclfenac Nw cmplete idilic (wrldwide) Any licensed drug Data analysis nging 5

6 GWAS: 197 Fluclxacillin DILI cases ( ) All f Eurpean ethnicity Patients and Methds 51 f these reprted previusly (DILIGEN) 6835 matched ppulatin cntrls Used Illumina HC and 1M chips fr gentyping Perfrmed imputatin t increase data cverage Fur digit HLA alleles and amin acid changes were inferred using SNP2HLA 6

7 Patients and DILI characteristics Gender (F/M) 133/64 (68% female) Mean Age (years) (+SD) Mean Time t nset frm first expsure (days) (+SD) Ttal days n drug (+SD) Chlestatic 74 (38%) Hepatcellular 39 (20%) Mixed 84 (43%) RUCAM scres 3-5 (pssible) 22 (11%) 6-8 (prbable) 90 (46%) >8 (highly prbable) 85 (43%) 7

8 New GWAS: Results MHC regin 8

9 HLA-B*57:01 majr Risk factr; allelic OR=36.6; 95% CI , p=2.67x10-97 ) Prtective effect frm HLA-B*07:02, C*07:02 and DQB1*03:01 HLA-B*57:03 is als a risk factr; OR=79.21; 95% CI , p=1.2x10-6 ) Shwn by cnditining n B*57:01 Results HLA-B alleles psitive fr valine-97 had largest effect size; OR 38.1 ( ) p = 9.7x10-97 ) Different t abacavir hypersensitivity where there is strng specificity fr HLA- B*57:01 nly 9

10 Amin acid sequences f HLA-B variants Residues 97, 114 and 116 appear crucial Abacavir: B*57:01 nly Fluclxacillin: B*57:01 and B*57:03 nly Neither assciates with B*58:01

11 HLA-B*5701 Serine 116 essential fr binding f abacavir purine grup Psitin 97 sits at the bttm f the peptide-binding cleft and is critical fr HLA prtein cnfrmatin and flding B*57:01 B*57:03 B*5701 B*5801 Illing et al. Nature 2012; 486:

12 Results Arg97 and Ser97 have significant prtective effects (OR= 0.43 P= 5.13x10-14 and OR= 0.53, P=9.82x10-7 ) Apprx. 20% f fluclxacillin DILI cases nt psitive fr B*57 HLA-A*02:02 enriched in these cases (OR 16.57, ( ) p = 0.008) Tw ther class I alleles, A*30:01 and B*13:02, als shw significant assciatins (P=0.009 and 0.017) Amxicillin and ther isxazlyl penicillin DILI cases dn t share HLA alleles seen in either the B*57 psitive r negative fluclxacillin DILI cases Suggests that there isn t a cmmn genetic risk factr relating t T cell respnse t the beta lactam structure 12

13 Summary Strng assciatin f Fluclxacillin DILI with HLA B*57:01 cnfirmed in an enlarged chrt Nvel assciatin with B*57:03 detected N evidence fr nn-hla genetic risk factrs Abacavir hypersensitivity is assciated nly with B*57:01 and appears t have a different mechanism frm fluclxacillin DILI 83% f DILI patients and 6% nrmal with HLA-B*5701/03; Genetic factrs can supprt the diagnsis f DILI in specific scenaris 13

14 SAE Cnsrtium, Ltd. 14