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Lookup NU author(s): Professor Ann DalyORCiD
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Background and aims Drug-induced liver injury (DILI) is a serious adverse drug event that is suspected to have a heritable component. We carried out a genome-wide association study of 783 individuals of European ancestry who experienced DILI due to more than 200 implicated drugs. Methods DILI patients from the US-based Drug-Induced Liver Injury Network (n=401) and three international registries (n=382) were genotyped with the Illumina 1Mduo BeadChip and compared with population controls (n=3001). Potential associations were tested in 307 independent Drug-Induced Liver Injury Network cases. Results After accounting for known major histocompatibility complex risk alleles for flucloxacillin-DILI and amoxicillin/clavulanate-DILI, there were no genome-wide significant associations, including in the major histocompatibility complex region. Stratification of DILI cases according to clinical phenotypes (injury type, latency, age of onset) also did not show significant associations. An analysis of hepatocellular DILI (n=285) restricted to 193 single-nucleotide polymorphisms previously associated with autoimmune disease showed a trend association for rs7574865, in the vicinity of signal transducer and activator of transcription 4 (STAT4) (P=4.5 x 10(-4)). This association was replicated in an independent cohort of 168 hepatocellular DILI cases (P=0.011 and 1.5 x 10(-5) for combined cohorts). No significant associations were found with stratification by other clinical or demographic variables. Conclusion Although not significant at the genome-wide level, the association between hepatocellular DILI and STAT4 is consistent with the emerging role of the immune system in DILI. However, the lack of genome-wide association study findings supports the idea that strong genetic determinants of DILI may be largely drug-specific or may reflect rare genetic variations, which were not assessed in our study. Pharmacogenetics and Genomics 22:784-795 (C) 2012 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins.
Author(s): Urban TJ, Shen YF, Stolz A, Chalasani N, Fontana RJ, Rochon J, Ge DL, Shianna KV, Daly AK, Lucena MI, Nelson MR, Molokhia M, Aithal GP, Floratos A, Pe'er I, Serrano J, Bonkovsky H, Davern TJ, Lee WM, Navarro VJ, Talwalkar JA, Goldstein DB, Watkins PB, Drug-Induced Liver Injury Network, DILIGEN, EUDRAGENE, Spanish DILI Registry, Int Serious Adverse Events Consort
Publication type: Article
Publication status: Published
Journal: Pharmacogenetics and Genomics
Year: 2012
Volume: 22
Issue: 11
Pages: 784-795
Print publication date: 01/11/2012
ISSN (print): 1744-6872
ISSN (electronic): 1744-6880
Publisher: Lippincott Williams & Wilkins
URL: http://dx.doi.org/10.1097/FPC.0b013e3283589a76
DOI: 10.1097/FPC.0b013e3283589a76
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