Association of Liver Injury From Specific Drugs, or Groups of Drugs, With Polymorphisms in HLA and Other Genes in a Genome-Wide Association Study

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dc.contributor.author Nicoletti, Paola
dc.contributor.author Aithal, Guruprasad P.
dc.contributor.author Bjornsson, Einar S.
dc.contributor.author Andrade, Raul J.
dc.contributor.author Sawle, Ashley
dc.contributor.author Arrese, Marco
dc.contributor.author Barnhart, Huiman X.
dc.contributor.author Bondon-Guitton, Emmanuelle
dc.contributor.author Hayashi, Paul H.
dc.contributor.author Bessone, Fernando
dc.contributor.author Carvajal, Alfonso
dc.contributor.author Cascorbi, Ingolf
dc.contributor.author Cirulli, Elizabeth T.
dc.contributor.author Chalasani, Naga
dc.contributor.author Conforti, Anita
dc.contributor.author Coulthard, Sally A.
dc.contributor.author Daly, Mark J.
dc.contributor.author Day, Christopher P.
dc.contributor.author Dillon, John F.
dc.contributor.author Fontana, Robert J.
dc.contributor.author Grove, Jane I.
dc.contributor.author Hallberg, Par
dc.contributor.author Hernandez, Nelia
dc.contributor.author Ibanez, Luisa
dc.contributor.author Kullak-Ublick, Gerd A.
dc.contributor.author Laitinen, Tarja
dc.contributor.author Larrey, Dominique
dc.contributor.author Lucena, M. Isabel
dc.contributor.author Maitland-van der Zee, Anke H.
dc.contributor.author Martin, Jennifer H.
dc.contributor.author Molokhia, Mariam
dc.contributor.author Pirmohamed, Munir
dc.contributor.author Powell, Elizabeth E.
dc.contributor.author Qin, Shengying
dc.contributor.author Serrano, Jose
dc.contributor.author Stephens, Camilla
dc.contributor.author Stolz, Andrew
dc.contributor.author Wadelius, Mia
dc.contributor.author Watkins, Paul B.
dc.contributor.author Floratos, Aris
dc.contributor.author Shen, Yufeng
dc.contributor.author Nelson, Matthew R.
dc.contributor.author Urban, Thomas J.
dc.contributor.author Daly, Ann K.
dc.contributor.author Int Drug-Induced Liver Injury Cons
dc.contributor.author Drug-Induced Liver Injury Network
dc.contributor.author Int Serious Adverse Events Consort
dc.date.accessioned 2017-06-01T08:09:01Z
dc.date.available 2017-06-01T08:09:01Z
dc.date.issued 2017-04
dc.identifier.citation Nicoletti , P , Aithal , G P , Bjornsson , E S , Andrade , R J , Sawle , A , Arrese , M , Barnhart , H X , Bondon-Guitton , E , Hayashi , P H , Bessone , F , Carvajal , A , Cascorbi , I , Cirulli , E T , Chalasani , N , Conforti , A , Coulthard , S A , Daly , M J , Day , C P , Dillon , J F , Fontana , R J , Grove , J I , Hallberg , P , Hernandez , N , Ibanez , L , Kullak-Ublick , G A , Laitinen , T , Larrey , D , Lucena , M I , Maitland-van der Zee , A H , Martin , J H , Molokhia , M , Pirmohamed , M , Powell , E E , Qin , S , Serrano , J , Stephens , C , Stolz , A , Wadelius , M , Watkins , P B , Floratos , A , Shen , Y , Nelson , M R , Urban , T J , Daly , A K , Int Drug-Induced Liver Injury Cons , Drug-Induced Liver Injury Network & Int Serious Adverse Events Consort 2017 , ' Association of Liver Injury From Specific Drugs, or Groups of Drugs, With Polymorphisms in HLA and Other Genes in a Genome-Wide Association Study ' , Gastroenterology , vol. 152 , no. 5 , pp. 1078-1089 . https://doi.org/10.1053/j.gastro.2016.12.016
dc.identifier.other PURE: 84979079
dc.identifier.other PURE UUID: 1bd530ae-0d4e-423e-b1ef-367e7cba75c5
dc.identifier.other WOS: 000397297700035
dc.identifier.other Scopus: 85016172481
dc.identifier.uri http://hdl.handle.net/10138/187587
dc.description.abstract BACKGROUND & AIMS: We performed a genome-wide association study (GWAS) to identify genetic risk factors for druginduced liver injury (DILI) from licensed drugs without previously reported genetic risk factors. METHODS: We performed a GWAS of 862 persons with DILI and 10,588 population-matched controls. The first set of cases was recruited before May 2009 in Europe (n = 137) and the United States (n = 274). The second set of cases were identified from May 2009 through May 2013 from international collaborative studies performed in Europe, the United States, and South America. For the GWAS, we included only cases with patients of European ancestry associated with a particular drug (but not flucloxacillin or amoxicillin-clavulanate). We used DNA samples from all subjects to analyze HLA genes and single nucleotide polymorphisms. 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% confidence interval [CI], 1.9 - 3.8; P = 2.4 x 10(-8)) and with rs72631567 on chromosome 2 (OR, 2.0; 95% CI, 1.6 - 2.5; P = 9.7 x 10(-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 was associated with cholestatic and mixed DILI as well as hepatocellular DILI. We identified an association between rs28521457 (within the lipopolysaccharide-responsive vesicle trafficking, beach and anchor containing gene) and only hepatocellular DILI (OR, 2.1; 95% CI, 1.6 - 2.7; P = 4.8 x 10(-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 = 7.1 x 10(-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. en
dc.format.extent 12
dc.language.iso eng
dc.relation.ispartof Gastroenterology
dc.rights.uri info:eu-repo/semantics/openAccess
dc.subject Medication
dc.subject Liver Damage
dc.subject Side Effect
dc.subject Anti-Fungal Agent
dc.subject INDUCED HEPATOTOXICITY
dc.subject CHOLESTATIC HEPATITIS
dc.subject PEPTIDE REPERTOIRE
dc.subject LRBA DEFICIENCY
dc.subject T-CELLS
dc.subject CLASS-I
dc.subject TICLOPIDINE
dc.subject POPULATION
dc.subject SUSCEPTIBILITY
dc.subject TERBINAFINE
dc.subject 3121 General medicine, internal medicine and other clinical medicine
dc.title Association of Liver Injury From Specific Drugs, or Groups of Drugs, With Polymorphisms in HLA and Other Genes in a Genome-Wide Association Study en
dc.type Article
dc.contributor.organization Clinicum
dc.contributor.organization Department of Medicine
dc.contributor.organization Keuhkosairauksien yksikkö
dc.description.reviewstatus Peer reviewed
dc.relation.doi https://doi.org/10.1053/j.gastro.2016.12.016
dc.relation.issn 0016-5085
dc.rights.accesslevel openAccess
dc.type.version publishedVersion

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