A Genome-Wide Association Study Identifies Potential Susceptibility Loci for Hepatotoxicity Due to Various Drugs

Abstract

Idiosyncratic drug-induced liver injury (DILI) is a leading cause of morbidity and mortality due to medication use yet is poorly studied, in part, due to its low incidence in the general population. Identification of genetic variants associated with these uncommon and difficult to diagnose adverse events could provide clues to underlying mechanisms. Hypothesis: Common genetic variants exist that contribute to DILI susceptibility from multiple drugs. Methods: DNA obtained from 783 individuals of European ancestry who experienced DILI attributed to >200 individual drugs were genotypedwith the Illumina 1Mor 1Mduo beadchip. Source of DNA samples included the following DILI registries: DILIN (401), DILIGEN (242), EUDRAGENE (89), and Malaga (51). Genome Wide Association (GWA) was performed using population controls (n=3001). Potential associations were tested for replication in 190 independent cases from DILIN. Results: GWA revealed a strong association within the MHC region (p 108), which did not replicate in validation cohorts composed of sufficient cases due to the same drug or class. Conclusion: Our replicated association between hepatocellular DILI and STAT4 supports the emerging role of the immune system in DILI susceptibility and suggests that common genetic variation may contribute to DILI susceptibility from multiple drugs. However, the generally negative GWA results suggest that there may be a preponderance of drug-specific genetic risk factors and/or rare genetic variation underlying DILI susceptibility. Therefore, we have begun whole exome and whole genome sequencing of DILI cases caused by the most frequent drugs in our cohorts in search of rarer, high-penetrance drug-specific risk factors.