Newly identified genetic variants associated with idiosyncratic drug-induced liver injury

Datasets of well characterized drug or herbal and dietary supplement-associated liver injury has provided a rich resource to identify genetic variants associated with hepatic injury that further supports the role of immune activation in drug-induced liver injury (DILI).

Using DNA microarrays, whole genome sequencing, HLA-restricted DNA sequencing with appropriate ethnically matched population controls have identified HLA-specific genetic variants for drugs or botanical compounds with the same HLA variant associated with different agents. In addition to HLAs, two genes involved with immune signaling were also identified: a functional PTPN22 variant associated with increased DILI risk to any agent or clinical presentation and a variant in ERAP2 hepatic gene expression that trims peptide in preparation for presentation in the HLA cleft increased the risk for DILI in amoxicillin-clavulanate DILI when present with known HLA risk alleles.

Variants in HLA and other genes involved in immune regulations further supports immune system activation in DILI. In the future, identifying these variants before exposure may minimize the risk for DILI events, help with assessment of drug causality for causing DILI and with greater understanding of DILI mechanisms, has important implication for future drug development.