Limited contribution of common genetic variants to risk for liver injury due to a variety of drugs
Year: 2012
Type: article
Study design: Observational Study
Abstract: 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=4.5×10(-4)). This association was replicated in an independent cohort of 168 hepatocellular DILI cases (P=0.011 and 1.5×10(-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.
Source: Pharmacogenetics and Genomics
Authors: Thomas J. Urban, Yufeng Shen, Andrew Stolz, Naga Chalasani, Robert J. Fontana, James Rochon, Dongliang Ge, Kevin V. Shianna, Ann K. Daly, M. Isabel Lucena, Matthew R. Nelson, Mariam Molokhia, Guruprasad P. Aithal, Aris Floratos, Itsik Pe’er, Jose Serrano, Herbert Bonkovsky, Timothy J. Davern, William M. Lee, Victor J. Navarro, Jayant A. Talwalkar, David B. Goldstein, Paul B. Watkins
Institutions: Duke University, University of Southern California, Indiana University Indianapolis, Indiana University School of Medicine, University of Michigan, Newcastle University, Hospital Clínico Universitario Virgen de la Victoria, Instituto de Investigación Biomédica de Málaga, Universidad de Málaga, King's College London, Nottingham University Hospitals NHS Trust, University of Nottingham, Columbia University, National Institute of Diabetes and Digestive and Kidney Diseases, University of North Carolina at Chapel Hill, Carolinas Medical Center, University of California, San Francisco, California Pacific Medical Center, The University of Texas Southwestern Medical Center, Thomas Jefferson University, Mayo Clinic
Language: English
Subfield: Pharmacology
Domain: Life Sciences
Open Access status: green
Funders: Wellcome Trust, Georgia Clinical and Translational Science Alliance, National Institute for Health and Care Research, National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, National Center for Research Resources, National Center for Advancing Translational Sciences
Awards: G113261452, G1333635724, IU Clinical Center: Drug Induced Liver Injury Network, G151959291, WTCCC2 core activities, G239052087, G2411765067, G244642860, Indiana Clinical and Translational Sciences Institute, G3229079822, G38283659, "Drug Induced Liver Injury Network", Research Network for Drug-Induced Liver Disease, Michigan Institute for Clinical and Health Research (MICHR) (UL1), Indiana Clinical and Translational Science Institute (UL1), G5043941941, G583498415, G6350184890, UNC Clinical and Translational Science Award, G7823966103, G801680829, Michigan Hepatotoxicity Clinical Research Network Renewal, G8225691149, The genetics of weight, BMI, adiposity and obesity, University of North Carolina Clinical Center for DILIN
OpenAlex ID: W1978127618