BACKGROUND & AIMS: Drug-induced liver injury (DILI), especially from antimicrobial agents, is an important cause of serious liver disease. Amoxicillin-clavulanate (AC) is a leading cause of idiosyncratic DILI, but little is understood about genetic susceptibility to this adverse reaction. METHODS: We performed a genome-wide association study using 822,927 single nucleotide polymorphism (SNP) markers from 201 White European and US cases of DILI following AC administration (AC-DILI) and 532 population controls, matched for genetic background. RESULTS: AC-DILI was associated with many loci in the major histocompatibility complex. The strongest effect was with an HLA class II SNP (rs9274407, P=4.8×10(-14)), which correlated with rs3135388, a tag SNP of HLA-DRB1*1501-DQB1*0602 that was previously associated with AC-DILI. Conditioned on rs3135388, rs9274407 is still significant (P=1.1×10(-4)). An independent association was observed in the class I region (rs2523822, P=1.8×10(-10)), related to HLA-A*0201. The most significant class I and II SNPs showed statistical interaction (P=.0015). High-resolution HLA genotyping (177 cases and 219 controls) confirmed associations of HLA-A*0201 (P=2×10(-6)) and HLA-DQB1*0602 (P=5×10(-10)) and their interaction (P=.005). Additional, population-dependent effects were observed in HLA alleles with nominal significance. In an analysis of autoimmune-related genes, rs2476601 in the gene PTPN22 was associated (P=1.3×10(-4)). CONCLUSIONS: Class I and II HLA genotypes affect susceptibility to AC-DILI, indicating the importance of the adaptive immune response in pathogenesis. The HLA genotypes identified will be useful in studies of the pathogenesis of AC-DILI but have limited utility as predictive or diagnostic biomarkers because of the low positive predictive values.
BACKGROUND & AIMS:Drug-induced liver injury (DILI), especially from antimicrobial agents, is an important cause of serious liver disease. Amoxicillin-clavulanate (AC) is a leading cause of idiosyncratic DILI, but little is understood about genetic susceptibility to this adverse reaction. METHODS: We performed a genome-wide association study using 822,927 single nucleotide polymorphism (SNP) markers from 201 White European and US cases of DILI following AC administration (AC-DILI) and 532 population controls, matched for genetic background. RESULTS:AC-DILI was associated with many loci in the major histocompatibility complex. The strongest effect was with an HLA class II SNP (rs9274407, P=4.8×10(-14)), which correlated with rs3135388, a tag SNP of HLA-DRB1*1501-DQB1*0602 that was previously associated with AC-DILI. Conditioned on rs3135388, rs9274407 is still significant (P=1.1×10(-4)). An independent association was observed in the class I region (rs2523822, P=1.8×10(-10)), related to HLA-A*0201. The most significant class I and II SNPs showed statistical interaction (P=.0015). High-resolution HLA genotyping (177 cases and 219 controls) confirmed associations of HLA-A*0201 (P=2×10(-6)) and HLA-DQB1*0602 (P=5×10(-10)) and their interaction (P=.005). Additional, population-dependent effects were observed in HLA alleles with nominal significance. In an analysis of autoimmune-related genes, rs2476601 in the gene PTPN22 was associated (P=1.3×10(-4)). CONCLUSIONS: Class I and II HLA genotypes affect susceptibility to AC-DILI, indicating the importance of the adaptive immune response in pathogenesis. The HLA genotypes identified will be useful in studies of the pathogenesis of AC-DILI but have limited utility as predictive or diagnostic biomarkers because of the low positive predictive values.
Authors: Shaun Purcell; Benjamin Neale; Kathe Todd-Brown; Lori Thomas; Manuel A R Ferreira; David Bender; Julian Maller; Pamela Sklar; Paul I W de Bakker; Mark J Daly; Pak C Sham Journal: Am J Hum Genet Date: 2007-07-25 Impact factor: 11.025
Authors: Raúl J Andrade; M Isabel Lucena; M Carmen Fernández; Gloria Pelaez; Ketevan Pachkoria; Elena García-Ruiz; Beatriz García-Muñoz; Rocio González-Grande; Angeles Pizarro; José Antonio Durán; Manuel Jiménez; Luis Rodrigo; Manuel Romero-Gomez; José María Navarro; Ramón Planas; Joan Costa; Africa Borras; Aina Soler; Javier Salmerón; Rafael Martin-Vivaldi Journal: Gastroenterology Date: 2005-08 Impact factor: 22.682
Authors: Raúl J Andrade; M Isabel Lucena; Neil Kaplowitz; Beatriz García-Muņoz; Yolanda Borraz; Ketevan Pachkoria; Miren García-Cortés; M Carmen Fernández; Gloria Pelaez; Luis Rodrigo; José A Durán; Joan Costa; Ramón Planas; Anabel Barriocanal; Carlos Guarner; Manuel Romero-Gomez; Teresa Muņoz-Yagüe; Javier Salmerón; Ramón Hidalgo Journal: Hepatology Date: 2006-12 Impact factor: 17.425
Authors: M Isabel Lucena; Raúl J Andrade; M Carmen Fernández; Ketevan Pachkoria; Gloria Pelaez; José A Durán; Macarena Villar; Luis Rodrigo; Manuel Romero-Gomez; Ramón Planas; Anabel Barriocanal; Joan Costa; Carlos Guarner; Sonia Blanco; José M Navarro; Fernando Pons; Agustin Castiella; Susana Avila Journal: Hepatology Date: 2006-10 Impact factor: 17.425
Authors: Paul I W de Bakker; Gil McVean; Pardis C Sabeti; Marcos M Miretti; Todd Green; Jonathan Marchini; Xiayi Ke; Alienke J Monsuur; Pamela Whittaker; Marcos Delgado; Jonathan Morrison; Angela Richardson; Emily C Walsh; Xiaojiang Gao; Luana Galver; John Hart; David A Hafler; Margaret Pericak-Vance; John A Todd; Mark J Daly; John Trowsdale; Cisca Wijmenga; Tim J Vyse; Stephan Beck; Sarah Shaw Murray; Mary Carrington; Simon Gregory; Panos Deloukas; John D Rioux Journal: Nat Genet Date: 2006-09-24 Impact factor: 38.330
Authors: Gideon M Hirschfield; Roger W Chapman; Tom H Karlsen; Frank Lammert; Konstantinos N Lazaridis; Andrew L Mason Journal: Gastroenterology Date: 2013-04-10 Impact factor: 22.682