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Adverse drug reactions (ADRs) account for 6-7 % of all hospital admissions and remain a major clinical problem. Type A ADR is dose-dependent and usually monogenic or oligogenic; an example is warfarin sensitivity, which causes excessive bleeding. A functional promoter polymorphism of vitamin K epoxide reductase complex subunit 1 was found to be associated with inter-individual differences in warfarin dosage and can explain the inter-ethnic differences in warfarin sensitivity. Prospective study of warfarin dosage requirements based on CYP2C9 and VKORC1 genotypes showed that pharmacogenetics-based dosing can improve the time to stable dosing, reduce adverse events and achieve high sensitivity.
Type B ADR is usually dose-independent, and historically referred to as being unpredictable and polygenic; an example is drug hypersensitivity. Several recent studies reported strong genetic associations between HLA and susceptibility to drug hypersensitivity. The genetic associations can be 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, a 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 of which HLA molecule presents an antigenic drug for T-cell activation. Pharmacogenomic study 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 genetic markers provides a plausible basis for developing tests to identify individuals at risk for drug hypersensitivity. Application of HLA-B*1502 genotyping as a screening tool for patient taking carbamazepine is now recommended by the Department of Health, Taiwan and by the US FDA. |
