Positive and negative associations of HLA class I alleles with allopurinol-induced SCARs in Koreans

Abstract

Recent investigations suggest genetic susceptibility of allopurinol-induced severe cutaneous adverse reactions (SCARs). However, the strength of association was variable according to phenotypes and ethnic backgrounds. To explore genetic markers for allopurinol-induced SCARs in Koreans, we genotyped human leukocyte antigen (HLA) class I alleles of 25 cases of allopurinol-induced SCARs (20 cases of drug-induced hypersensitivity syndrome and five cases of Stevens-Johnson syndrome/toxic epidermal necrolysis) and 57 patients tolerant to allopurinol. Frequencies of B*5801 [92.0 vs. 10.5%, P(c)=2.45×10(-11), odds ratio (OR)=97.8], Cw*0302 (92.0 vs. 12.3%, P(c)=9.39×10(-11), OR=82.1), and A*3303 (88.0 vs. 26.3%, P(c)=3.31×10(-6), OR=20.5) were significantly higher in SCARs compared with tolerant controls. In contrast, A*0201 was not found in SCARs patients despite relatively high frequency in tolerant controls (29.8%). We found strong positive association of HLA-B*5801 and negative association of HLA-A*0201 with the development of allopurinol-induced SCARs in the Korean population.

An effective strategy to prevent allopurinol-induced hypersensitivity by HLA typing

“…14,15 Most exciting is that our study is the first to provide substantial evidence to support the effectiveness of a tolerance induction protocol to prevent the development of allopurinol-induced hypersensitivity response in a group of high-risk patients. This unique design is based on the idea that primary prevention of hypersensitivity reaction can be attained by inducing immunological tolerance with the introduction of a "desensitization protocol."…”

“…In particular, 100% of Han Chinese and Thai patients with allopurinol-induced SCARs showed positivity for HLA-B*58:01. 6,13,14 In our previous case-control study we observed a very strong positive association between allopurinol-induced SCARs and the HLA-B*58:01 allele in a Korean population (odds ratio = 97.8; 95% confidence interval: 18.3-521.5).…”

Oxypurinol Directly and Immediately Activates the Drug-Specific T Cells via the Preferential Use of HLA-B*58:01

“…Because the HLA-B*58:01 allele is highly associated with ALPinduced SCAR, we also hypothesized that HLA-B*58:01 plays a role in this interaction (2)(3)(4)(5). Our recent data also revealed that the presence of HLA-B*58:01 is an important immunogenic factor in generating the ALP/OXP-specific T cell response (18).…”

Evolving models of the immunopathogenesis of T cell–mediated drug allergy: The role of host, pathogens, and drug response

“…90 This association has since been identified in Thai, Korean, and Japanese populations and it is estimated that HLA-B*58:01 explains approximately 60% of allopurinol inducted IM-ADRs in European and Japanese populations. [91][92][93][94][95] Unlike abacavir or carbamazepine, both of which drive T-cell reactivity in the absence of drug modification, both allopurinol and its metabolite oxypurinol have been shown to contribute to the pathogenesis of allopurinol associated IM-ADR. In vitro studies have demonstrated that T cells isolated from both allopurinol-naïve, HLA-B*58:01-positive individuals and from patients with history of allopurinol induced IM-ADR rapidly proliferate and become activated following exposure to allopurinol or oxypurinol.…”