HLA-B Genotyping to Detect Carbamazepine-Induced Stevens-Johnson Syndrome: Implications for Personalizing Medicine

Abstract

Preventing severe adverse drug reactions by identifying people at risk with a simple genetic test is the goal of many pharmacogenomic studies. Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are related, life-threatening cutaneous adverse reactions, most often caused by medication. The overall incidence and the commonly offending drugs vary among different ethnic populations. Susceptibility to such idiosyncratic reactions is thought to be genetically determined and immune mediated. Finding a strong genetic association between a particular human leukocyte antigen (HLA)-B allele and the reaction to a specific drug provides evidence that the pathogenesis of the severe cutaneous adverse drug reactions involves major histocompatibility complex-restricted presentation of a drug or its metabolites for T-cell activation. In the case of carbamazepine-induced SJS/TEN, the tight association of the HLA-B*1502 allele (sensitivity 100%, specificity 97% and odds ratio 2504) provides a plausible basis for further development of such a test to identify individuals at risk of developing this life-threatening condition.

A comparison of major histocompatibility complex SNPs in Han Chinese residing in Taiwan and Caucasians

“…cgi), and MHC studies [9,11,18]. Comparing the prevalence of inherited diseases in Han Chinese and Caucasian populations, atherosclerosis related to AIF1 and psoriasis related to C6orf18 are more prevalent in Caucasians [26,27]; allopurinolinduced severe cutaneous adverse reaction related to BAT3 [18] and hepatitis B virus related to HLA-DRA are more prevalent in Han Chinese [28,29]. Furthermore, we also investigated genomic regions highly linked to the 101 SNPs and found that some are related to the etiology of diseases such as nasopharyngeal carcinoma, which is highly prevalent in Asian populations.…”

Severe Cutaneous Adverse Reactions

“…The risk of disease from a genetic polymorphism is influenced by its prevalence. The HLA-B*1502 allele frequency is 4.8 to 12.8% in Southeast Asians compared to 0-0.1% observed in Northern Europeans [58]. For instance, HLA-B*1502 is of low prevalence in Caucasians and hence, if it is a true susceptibility allele, a very large sample size is required in this population to detect a significant odds ratio of sufficient power.…”

“…In Western countries, the most commonly implicated agents of SJS/TEN were NSAIDs and sulphonamides [17]. In contrast, carbamazepine was found to be the leading cause of SJS/TEN in Southeast Asian countries, including India, Malaysia, Singapore, Taiwan and Hong Kong [58]. Interestingly, carbamazepine in Western countries causes more cases of DIHS than SJS/TEN.…”

“…Genetic screening for HLA-B*1502 in a high risk population such as the Han Chinese has a 100% sensitivity and 97% specificity and its presence confers a 7.7% positive predictive value for carbamazepine-induced SJS/TEN whereas its absence has a 100% negative predictive value [58]. The odds ratio in test-positive Chinese patients to test-negative patients of having carbamazepine-induced SJS/TEN is >3200.…”

Prevention of severe cutaneous adverse drug reactions: the emerging value of pharmacogenetic screening

“…8 By contrast, carbamazepine is the leading cause of Stevens-Johnson syndrome in Southeast Asian countries, including India, Malaysia, Singapore, Taiwan and Hong Kong. 9 Carbamazepine in Western countries causes more instances of drug-induced hypersensitivity syndrome than overlapping Stevens-Johnson syndrome and toxic epidermal necrolysis. Allopurinol is also a frequent cause of overlapping StevensJohnson syndrome and toxic epidermal necrolysis and of drug-induced hypersensitivity syndrome, but it does not appear to have an ethnic bias.…”