Pharmacogenetics of cutaneous adverse drug reactions

Abstract

Drug-induced hypersensitivity reactions are of major medical concern because they are associated with high morbidity and high mortality. In addition, individual patients' reactions are impossible to predict in each patient. In the field of severe cutaneous adverse drug reactions (cutaneous ADR) such as Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug-induced hypersensitivity syndrome (DHIS) or drug rash with eosinophilia and systemic symptoms (DRESS), major advances have recently been gained through studies of an association between HLA alleles and drug hypersensitivity induced by specific drugs. The results of these pharmacogenomic studies allow prediction of the risk of adverse reactions in patients treated with certain drugs, including carbamazepine and other aromatic antiepileptic drugs, allopurinol and abacavir. However, different ethnic populations show variations in the genetic associations. A strong association between carbamazepine-induced SJS ⁄ TEN and HLA-B*1502 has been found in Southeast Asian patients but not in Caucasian and Japanese patients. Moderate associations between aromatic amine anticonvulsants and other HLA alleles have been proposed in Japanese patients. In contrast, HLA-B*5801 was found to be associated with allopurinol-induced cutaneous ADR, including SJS ⁄ TEN and DIHS ⁄ DRESS, in Caucasian and Asian patients, including the Japanese. These differences may, at least in part, be due to the differences in allele frequency in different ethnic populations. This article reviews the progress in pharmacogenomics, associated mainly with carbamazepine and allopurinol in different ethnic populations. Pharmacogenetic screening based on associations between adverse reactions and specific HLA alleles helps to avoid serious conditions associated with drug hypersensitivity.

Patterns and Outcomes of Cutaneous Adverse Drug Reactions in a Hospital Based Study

“…Current studies indicate that HLAB*1502 is a marker for carbamazepine-induced SJS⁄TEN in Southeast Asian popula ons, where the prevalence of HLA-B*1502 is rela vely high. 22 The role of cor costeroids in the treatment of SJS/TEN is controversial. Earlier studies suggested increased morbidity and mortality.…”

Development and partial validation of a mouse model for predicting drug hypersensitivity reactions

“…There has been a significant amount of interest in HLA variants, particularly since genome-wide association studies have revealed associations between specific HLA alleles and drug hypersensitivity responses, e.g. abacavir/HLA-B*5701, allopurinol/HLA-B*5801, and carbamazepine HLA-B*1502 (Aihara, 2011;Wei et al, 2012). Recent studies have demonstrated that, in the case of abacavir, binding of abacavir to the peptide binding cleft of the HLA can alter the peptide repertoire presented to T-cells, which can result in an allogenic-like reaction (Illing et al, 2012;Norcross et al, 2012;Ostrov et al, 2012).…”

Personalized Medicine, Availability, and Group Disparity: An Inquiry into How Physicians Perceive and Rate the Elements and Barriers of Personalized Medicine

“…More recently, certain human leukocyte antigens (HLA) have been associated with delayed drug sensitivity to which the Food and Drug Administration (FDA, USA) has responded by recommending testing for specific HLA genes for carbamazepine and abacavir [59]. The variant HLA gene that can lead to a life threatening skin disorder when taking carbamazepine is primarily present in people from Asian countries and is virtually absent in people without Asian ancestry [60]. Thus, those physicians who perceive racial inequality may be cognizant of these issues.…”