Genetics of immune-mediated adverse drug reactions: a comprehensive and clinical review

Adverse drug reactions (ADRs) are common and are a major problem in drug therapy. Patients experience unnecessary morbidity and mortality whilst many effective drugs are withdrawn because of ADRs in a minority of patients. Recent studies have demonstrated significant associations between human leukocyte antigens (HLA) and predisposition to ADRs such as drug-induced skin injury (DISI) and drug-induced liver injury (DILI). HLA-B*58:01 has been significantly associated with allopurinol-induced hypersensitivity. Associations between HLA and carbamazepine hypersensitivity reactions demonstrate both ethnicity and phenotype specificity; with HLA-B*15:02 associated with Stevens-Johnson syndrome and toxic epidermal necrolysis in South East Asian patients only whilst HLA-A*31:01 is associated with all phenotypes of hypersensitivity in multiple ethnicities. Studies of ximelagatran, an oral direct thrombin inhibitor withdrawn because of hepatotoxicity, found associations between HLA-DRB1*07:01 and HLA-DQA1*02:01 and ximelagatran DILI. Interestingly, HLA-B*57:01 is associated with both abacavir DISI and flucloxacillin DILI but the reasons for the different phenotype of ADR remains unknown. Pharmacogenetic screening for HLA-B*57:01 prior to abacavir therapy has significantly reduced the incidence of abacavir hypersensitivity syndrome in clinical practice. No other HLA associations have been translated into clinical practice because of multiple reasons including failure to replicate, inadequate sample sizes, and our lack of understanding of pathophysiology of ADRs. Here, we review genetic associations that have been reported with ADRs and discuss the challenges that scientists, clinicians, pharmaceutical industry and regulatory agencies face when attempting to translate these associations into clinically valid and cost-effective tests to reduce the burden of ADRs in future.