Genetic risk factors in the development of idiosyncratic drug-induced liver injury

ABSTRACT

Introduction: Idiosyncratic drug-induced liver injury (DILI) is a challenging condition with widespread implications. The underlying mechanism of DILI is not yet fully elucidated, but genetic predispositions are believed to contribute to DILI susceptibility. The identification of genetic risk factors has been a goal in DILI research for more than two decades.

Areas covered: Here we provide an overview of genetic studies in DILI performed to date and outline polymorphisms identified to have a potential role in DILI development. This review covers both earlier candidate gene studies and more recent genome-wide association studies. The clinical applications of these findings are also discussed.

Expert opinion: Various polymorphisms have been identified as associated with DILI susceptibility, but all of these have not been confirmed in independent studies or contradictive findings are available. Genome-wide significant associations between distinct HLA risk alleles and DILI due to specific causative agents strengthen the hypothesis that DILI is partially immune-mediated. These HLA alleles generally have low positive predictive value and are therefore not useful in preemptive tests to reduce DILI incidences, but can aid DILI diagnosis and clinical decision-making.

KEYWORDS:

• Candidate gene studies
• genome-wide association studies
• drug metabolism
• pharmacogenetics
• pharmacogenomics
• human leukocyte antigen

Article highlights

• A number of polymorphisms in genes involved in drug metabolism have been associated with idiosyncratic drug-induced liver injury (DILI) development in candidate gene studies, but have not been confirmed in more recent genome-wide association (GWA) studies.

• Contradictive findings in DILI genetic studies can stem from small study cohorts, variations in study parameters and ethnic backgrounds. Furthermore, GWA studies apply a very high threshold for genome-wide significance.

• DILI risk alleles with genome-wide significance are mostly limited to distinct human leukocyte antigen (HLA) alleles associated with specific causative agents, which supports the notion of the immune system playing an integral role in DILI.

• HLA risk alleles can support or refute a DILI diagnosis and provide guidance in the diagnostic context leading to enhanced accuracy and confidence. However, HLA screening cannot currently replace clinical judgment.

• DILI is a relatively rare condition and collaborative efforts are required to perform well-powered genetic studies. Larger study cohorts are more likely to identify potential risk alleles outside the HLA region that could shed light on the underlying mechanism of DILI.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

A peer reviewer of this manuscript discloses receiving personal fees from Novartis for consultancy on drug-induced liver injury with ribociclib (outside genetics). Peer reviewers on this manuscript have no other relevant financial or other relationships to disclose.

Additional information

Funding

This work was supported by grants of Instituto de Salud Carlos III cofounded by Fondo Europeo de Desarrollo Regional – FEDER (contract numbers: PI16/01748, PI19/00883 and PY18-3364). CIBERehd is funded by Instituto de Salud Carlos III.