RT Journal Article
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.
A1 Nicoletti, Paola
A1 Aithal, Guruprasad P.
A1 Bjornsson, Einar S.
A1 Andrade-Bellido, Raúl Jesús
A1 Sawle, Ashley
A1 Arrese, Marco
A1 Barnhart, Huiman X
A1 Bondon-Guitton, Emmanuelle
A1 Hayashi, Paul H.
A1 Bessone, Fernando
A1 Carvajal, Alfonso
A1 Cascorbi, Ingolf
A1 Cirulli, Elizabeth T
A1 Chalasani, Naga
A1 Conforti, Anita
A1 Coulthard, Sally A
A1 Daly, Mark J
A1 Day, Christopher P
A1 Dillon, John F
A1 Fontana, Robert J.
A1 Grove, Jane I.
A1 Hallberg, Pär
A1 Hernandez, Nelia
A1 Ibáñez, Luisa
A1 Kullak-Ublick, Gerd A
A1 Laitinen, Tarja
A1 Larrey, Dominique
A1 Lucena-González, María Isabel
A1 Maitland-van der Zee, Anke H
A1 Martin, Jennifer H
A1 Molokhia, Mariam
A1 Pirmohamed, Munir
A1 Powell, Elizabeth E
A1 Qin, Shengying
A1 Serrano, Jose
A1 Stephens, Camilla
A1 Stolz, Andrew
A1 Wadelius, Mia
A1 Watkins, Paul B
A1 Floratos, Aris
A1 Shen, Yufeng
A1 Nelson, Matthew R
A1 Urban, Thomas J
A1 Daly, Ann K.
K1 Hígado - Heridas y lesiones
K1 Hepatotoxicidad
K1 Medicamentos - Efectos secundarios
K1 Genómica
K1 Agentes antifúngicos
AB Background & AimsWe 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.MethodsWe 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.
AB ResultsWe 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 × 10−8) and with rs72631567 on chromosome 2 (OR, 2.0; 95% CI, 1.6−2.5; P = 9.7 × 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 × 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 × 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.ConclusionsIn 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
PB Elsevier
YR 2017
FD 2017-04
LK https://hdl.handle.net/10630/40473
UL https://hdl.handle.net/10630/40473
LA eng
NO Nicoletti P, Aithal GP, Bjornsson ES, Andrade RJ, Sawle A, Arrese M, Barnhart HX, Bondon-Guitton E, Hayashi PH, Bessone F, Carvajal A, Cascorbi I, Cirulli ET, Chalasani N, Conforti A, Coulthard SA, Daly MJ, Day CP, Dillon JF, Fontana RJ, Grove JI, Hallberg P, Hernández N, Ibáñez L, Kullak-Ublick GA, Laitinen T, Larrey D, Lucena MI, Maitland-van der Zee AH, Martin JH, Molokhia M, Pirmohamed M, Powell EE, Qin S, Serrano J, Stephens C, Stolz A, Wadelius M, Watkins PB, Floratos A, Shen Y, Nelson MR, Urban TJ, Daly AK; International Drug-Induced Liver Injury Consortium, Drug-Induced Liver Injury Network Investigators, and International Serious Adverse Events Consortium. 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 2017 Apr;152(5):1078-1089
DS RIUMA. Repositorio Institucional de la Universidad de Málaga
RD 19 ene 2026