TY - JOUR
T1 - Association of Liver Injury From Specific Drugs, or Groups of Drugs, With Polymorphisms in HLA and Other Genes in a Genome-wide Association Study
AU - Nicoletti, Paola
AU - Aithal, Guruprasad P.
AU - Bjornsson, Einar S.
AU - Andrade, Raul J.
AU - Sawle, Ashley
AU - Arrese, Marco
AU - Barnhart, Huiman X.
AU - Bondon-Guitton, Emmanuelle
AU - Hayashi, Paul H.
AU - Bessone, Fernando
AU - Carvajal, Alfonso
AU - Cascorbi, Ingolf
AU - Cirulli, Elizabeth T.
AU - Chalasani, Naga
AU - Conforti, Anita
AU - Coulthard, Sally A.
AU - Daly, Mark J.
AU - Day, Christopher P.
AU - Dillon, John F.
AU - Fontana, Robert J.
AU - Grove, Jane I.
AU - Hallberg, Pär
AU - Hernández, Nelia
AU - Ibáñez, Luisa
AU - Kullak-Ublick, Gerd A.
AU - Laitinen, Tarja
AU - Larrey, Dominique
AU - Lucena, M. Isabel
AU - Maitland-van der Zee, Anke H.
AU - Martin, Jennifer H.
AU - Molokhia, Mariam
AU - Pirmohamed, Munir
AU - Powell, Elizabeth E.
AU - Qin, Shengying
AU - Serrano, Jose
AU - Stephens, Camilla
AU - Stolz, Andrew
AU - Wadelius, Mia
AU - Watkins, Paul B.
AU - Floratos, Aris
AU - Shen, Yufeng
AU - Nelson, Matthew R.
AU - Urban, Thomas J.
AU - Daly, Ann K.
AU - International DILI consortium (iDILIC)
AU - Drug-induced liver injury network (DILIN) investigators
AU - International Serious Adverse Events Consortium (iSAEC)
N1 - The genome-wide association study, HLA genotyping and iDILIC case enrollment and sample collection was funded by the International Serious Adverse Events Consortium with (Phase 2) membership support from Abbott, Amgen, Daiichi-Sankyo, GlaxoSmithKline,Merck, Novartis, Pfizer, Roche, Sanofi-Aventis, Takeda, and the Wellcome Trust. This is a summary of independent research partly (the DILIGEN and iDILIC sample collection) funded by the National Institute for Health Research (NIHR) Nottingham Digestive Diseases Biomedical Research Unit at the Nottingham University Hospitals NHS Trust and University of Nottingham. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. The DILIN (https://dilin.dcri.duke.edu/) is supported by the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health (NIH) as a Cooperative Agreement (U01s) under grants: U01-DK065176 (Duke), U01-DK065201 (UNC), U01-DK065184 (Michigan), U01-DK065211 (Indiana), U01DK065193 (UConn), U01-DK065238 (UCSF/CPMC), U01-DK083023 (UTSW), U01-DK083027 (TJH/UPenn), U01-DK082992 (Mayo), U01-DK083020 (USC), U01-DK100928 (Icahn). Additional funding is provided by CTSA grants UL1 RR025761 (Indiana), UL1 TR001111 (UNC), and UL1 UL1 RR024986 (UMich). The EUDRAGENE collaboration received support from the EC 5th Framework program (QLRI-CT-2002-02757). The Spanish DILI Registry is partly funded by the Spanish Medicine Agency, Fondo Europeo de Desarrollo Regional - FEDER (P10-CTS-6470, FIS PI12/00378). CIBERehd is funded by Instituto de Salud Carlos III. The Swedish case collection (SWEDEGENE) has received support from the Swedish Medical Products Agency, the Swedish Society of Medicine (2008-21619), Swedish Research Council (Medicine 521-2011-2440), and Swedish Heart and Lung Foundation (20120557). MM was supported by the National Institute for Health Research (NIHR) Biomedical Research Centre at Guy's and St Thomas' NHS Foundation Trust and King's College London. LI was supported by Instituto de Salud Carlos III (EC08/00250). MA was supported by CONICYT PIA/Basal PFB12.
The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
PY - 2017/4
Y1 - 2017/4
N2 - Background & Aims: We performed a genome-wide association study (GWAS) to identify genetic risk factors for drug-induced liver injury (DILI) from licensed drugs without previously reported genetic risk factors.Methods: We performed a GWAS of 862 persons with DILI and 10588 population-matched controls. The first set of cases was recruited prior to May 2009 in Europe (n=137) or the USA (n=274). The second set of cases were identified from May 2009 through May 2013 from international collaborative studies performed in Europe, the USA and South America. For the GWAS, we included only cases of European ancestry associated with a particular drug (but not flucloxacillin or amoxicillin-clavulanate). We used DNA samples from all subjects to analyze human leukocyte antigen (HLA) genes and single nucleotide polymorphisms (SNPs). After the discovery analysis was concluded, we validated our findings using data from 283 European patients with diagnosis of DILI associated with various drugs.Results: We associated DILI with rs114577328 (a proxy for A*33:01 a HLA class I allele; odds ratio [OR], 2.7; 95% CI, 1.9-3.8; P=2.4x10-8) and with rs72631567 on chromosome 2 (OR, 2.0; 95% CI, 1.6-2.5; P=9.7x10-9). The association with A*33:01 was mediated by large effects for terbinafine-, fenofibrate-, and ticlopidine-related DILI. The variant on chromosome 2 was associated with DILI from a variety of drugs. Further phenotypic analysis indicated that the association between DILI and A*33:01 was significant, genome wide, for cholestatic and mixed DILI, but not for hepatocellular DILI; the polymorphism on chromosome 2 associated with cholestatic and mixed DILI as well as hepatocellular DILI. We identified an association between rs28521457 (within the LRBA gene) and only hepatocellular DILI (OR, 2.1; 95% CI, 1.6-2.7; P=4.8x10-9). We did not associate any specific drug classes with genetic polymorphisms, except for statin-associated DILI, which was associated with rs116561224 on chromosome 18 (OR=5.4; 95% CI, 3.0-9.5; P=7.1x10-9). We validated the association between A*33:01 terbinafine- and sertraline-induced DILI. We could not validate the association between DILI and rs72631567, rs28521457, or rs116561224.Conclusions: In a GWAS of persons of European descent with DILI, we associated HLA-A*33:01 with DILI due to terbinafine and possibly fenofibrate and ticlopidine. We identified polymorphisms that appear to be associated with DILI from statins, as well as 2 non-drug-specific risk factors.
AB - Background & Aims: We performed a genome-wide association study (GWAS) to identify genetic risk factors for drug-induced liver injury (DILI) from licensed drugs without previously reported genetic risk factors.Methods: We performed a GWAS of 862 persons with DILI and 10588 population-matched controls. The first set of cases was recruited prior to May 2009 in Europe (n=137) or the USA (n=274). The second set of cases were identified from May 2009 through May 2013 from international collaborative studies performed in Europe, the USA and South America. For the GWAS, we included only cases of European ancestry associated with a particular drug (but not flucloxacillin or amoxicillin-clavulanate). We used DNA samples from all subjects to analyze human leukocyte antigen (HLA) genes and single nucleotide polymorphisms (SNPs). After the discovery analysis was concluded, we validated our findings using data from 283 European patients with diagnosis of DILI associated with various drugs.Results: We associated DILI with rs114577328 (a proxy for A*33:01 a HLA class I allele; odds ratio [OR], 2.7; 95% CI, 1.9-3.8; P=2.4x10-8) and with rs72631567 on chromosome 2 (OR, 2.0; 95% CI, 1.6-2.5; P=9.7x10-9). The association with A*33:01 was mediated by large effects for terbinafine-, fenofibrate-, and ticlopidine-related DILI. The variant on chromosome 2 was associated with DILI from a variety of drugs. Further phenotypic analysis indicated that the association between DILI and A*33:01 was significant, genome wide, for cholestatic and mixed DILI, but not for hepatocellular DILI; the polymorphism on chromosome 2 associated with cholestatic and mixed DILI as well as hepatocellular DILI. We identified an association between rs28521457 (within the LRBA gene) and only hepatocellular DILI (OR, 2.1; 95% CI, 1.6-2.7; P=4.8x10-9). We did not associate any specific drug classes with genetic polymorphisms, except for statin-associated DILI, which was associated with rs116561224 on chromosome 18 (OR=5.4; 95% CI, 3.0-9.5; P=7.1x10-9). We validated the association between A*33:01 terbinafine- and sertraline-induced DILI. We could not validate the association between DILI and rs72631567, rs28521457, or rs116561224.Conclusions: In a GWAS of persons of European descent with DILI, we associated HLA-A*33:01 with DILI due to terbinafine and possibly fenofibrate and ticlopidine. We identified polymorphisms that appear to be associated with DILI from statins, as well as 2 non-drug-specific risk factors.
KW - Medication
KW - Liver damage
KW - side effects
KW - Anti-fungal agent
U2 - 10.1053/j.gastro.2016.12.016
DO - 10.1053/j.gastro.2016.12.016
M3 - Article
C2 - 28043905
SN - 0016-5085
VL - 152
SP - 1078
EP - 1089
JO - Gastroenterology
JF - Gastroenterology
IS - 5
ER -