Genetic susceptibility and pharmacogenomics of severe cutaneous adverse drug reactions

Abstract

Several recent studies have reported strong genetic associations between HLA-B and susceptibility to drug hypersensitivity. The genetic associations are often drug-specific; HLA-B*1502 is associated with carbamazepine-induced Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS⁄TEN), HLA-B*5701 with abacavir hypersensitivity, and HLA-B*5801 with allopurinol-induced severe cutaneous adverse reactions. The genetic association can also be phenotype-specific; B*1502 is associated solely with carbamazepine-SJS⁄TEN, and not with either maculopapular eruption or hypersensitivity syndrome. Furthermore, genetic association can be ethnicity-specific; carbamazepine-SJS⁄TEN associated with B*1502 is seen in Southeast Asians but not in Caucasians or Japanese, which can be explained by the difference in allele frequencies among populations. The strong genetic association suggests a direct involvement of HLA in the pathogenesis of drug hypersensitivity, in which the HLA molecule presents an antigenic drug for T-cell activation. Pharmacogenomic study has identified an unusual form of granulysin secreted by cytotoxic T lymphocytes and natural killer cells responsible for the disseminated keratinocyte death in Stevens-Johnson syndrome and toxic epidermal necrolysis. The high sensitivity⁄specificity of some of these genetic markers provides a plausible basis for developing tests to identify individuals at risk for these life-threatening conditions in some populations. Application of HLA-B*1502 and HLA-B*5701 genotyping as a screening tool for patients taking carbamazepine and abacavir, respectively, has reduced the incidence of these adverse drug reactions.