HLA-B*1502 allele is associated with a cross-reactivity pattern of cutaneous adverse reactions to antiepileptic drugs.

Department of Neurology, Institute of Neurology, State Key Laboratory of Medical Neurobiology, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, China.
The Journal of international medical research (Impact Factor: 1.1). 02/2012; 40(1):377-82. DOI: 10.1177/147323001204000140
Source: PubMed

ABSTRACT The US Food and Drug Administration has recommended genetic screening for the human leucocyte antigen-B (HLA-B)*1502 allele in patients of Asian ethnicity before starting carbamazepine therapy, to avoid the fatal adverse treatment-related events associated with this drug. The association between cross-reactivity to antiepileptic drugs (AEDs) and the HLA-B*1502 allele has been only rarely reported. Here, two cases of cross-reactivity to AEDs, where cutaneous adverse drug reactions (cADRs) developed in female Han Chinese patients with epilepsy who tested positive for the HLA-B*1502 allele, are described. If the genetic association could be confirmed in larger studies, the HLA-B*1502 allele should be tested for in any patient experiencing cADRs, to avoid crossreactivity to AEDs.

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    ABSTRACT: Backgroud The cross-allergic reactions among aromatic antiepileptic drugs (AEDs) are common, but little is known about the genetic mechanisms. Purpose The aim of this study was to investigate the genetic associations of the human leukocyte antigen (HLA) genes with the cross-reactivity of cutaneous adverse drug reactions (cADRs) induced by different aromatic AEDs. Methods We reviewed 60 Chinese patients with a history of cADRs induced by an aromatic AED, and which re-challenged other aromatic AEDs as an alternative to the causative AED owing to some particular reasons. According to whether developing another episode of cADRs, these patients were automatically divided into the cross-reactivity group and tolerant control group. High-resolution HLA-A, -B, -DRB1 genotyping were performed for each patient. Results One out of 10 patients (10%, 1/10) carried the HLA-A*2402 allele in the cross-reactivity group. However, 23 patients (46%, 23/50) carried this allele in the tolerant control group. The difference of the HLA-A*2402 allele between the two groups is statistically significant (P = 0.040, OR = 0.130, 95% CI: 0.015-1.108). In addition, the frequency differences of other HLA alleles between the two groups, including the HLA-B*1502 allele, did not reach statistical significance (P > 0.05). Conclusions The HLA genes contribute to the genetic susceptibility of the cross-reactivity of cADRs among aromatic AEDs. Our results suggest that HLA-B*1502 is not a major responsible allele for the cross-reactivity of cADRs to aromatic AEDs, but the HLA-A*2402 allele may be a protective marker for the cross-allergic reactions among aromatic AEDs in Han Chinese. Further studies are warranted to test the potential predictive value of the HLA-A*2402 allele in future.
    Epilepsy Research 08/2014; 108(6). DOI:10.1016/j.eplepsyres.2014.03.017 · 2.19 Impact Factor
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    ABSTRACT: Antiepileptic drugs can induce potentially life-threatening hypersensitivity reactions such as Stevens-Johnson syndrome at a frequency of one in 10,000 to one in 1000 treated patients. There is a considerable cross-reactivity among different antiepileptic drugs but the mechanisms are not known. In this review we have summarized current evidence on antiepileptic drug-induced hypersensitivity reactions and performed meta-analyses of published case-control studies that investigated associations between HLA alleles and several antiepileptic drugs in diverse populations. As the heterogeneity between studies was high, we conducted subsequent subgroup analyses and showed that HLA-B*15:02 was associated with carbamazepine, lamotrigine and phenytoin-induced Stevens-Johnson syndrome in Asian populations indicating that pretreatment testing may prevent cross-reactivity. Additionally, we explored the potential of new, high-throughput technologies that may help to understand the mechanisms and predict the risk of adverse drug reactions in the future.
    Pharmacogenomics 04/2014; 15(6):857-868. DOI:10.2217/pgs.14.65 · 3.43 Impact Factor
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    ABSTRACT: A considerable heterogeneity exists in the literature on the role of different HLA alleles in carbamazepine (CBZ)-induced cutaneous adverse drug reactions (cADRs) of varying severity among diverse ethnic groups. The aim of the present study was to understand and summarize this heterogeneity and evaluate the contribution of common HLA alleles to susceptibility to cADRs in patients treated with CBZ through a meta-analysis. A literature search of Embase, Medline, Web of Knowledge, and Cochrane database of systematic reviews was performed up to 28 September 2013. A total of 20 reports were identified as eligible studies, which included 720 CBZ-intolerant [Stevens-Johnson syndrome and toxic epidermal necrolysis (bullous lesions): n=277; hypersensitivity syndrome/maculopapular exanthema (nonbullous lesions): n=359; others: n=84], 1512 CBZ-tolerant, and 1113 normal controls. We observed HLA-A*3101 and HLA-B*1502 as risk markers and HLA-B*4001 as a protective marker for susceptibility to cADRs when comparing intolerant with tolerant patients. Stratification by clinical outcome showed HLA-B*1502 and HLA-B*1511 as risk and HLA-A*2402 as protective markers for bullous lesions in the Asians [HLA-B*1502: odds ratio (OR)=80.70; 95% confidence interval (CI)=45.62-142.77; P=1.8×10; I=33%, HLA-B*1511: OR=17.43; 95% CI=3.12-97.40; P=1.1×10; I=0%, HLA-A*2402: OR=0.27; 95% CI=0.11-0.64; P=2.7×10; I=0%]. Furthermore, HLA-A*3101 was observed to be a universal risk marker, irrespective of cADR type [OR (bullous lesions)=5.65; 95% CI =2.70-11.78; P=4.03×10; I=49%, OR (nonbullous lesions)=8.58; 95% CI=5.55-13.28; P=4.46×10; I=0%]. Sensitivity analysis showed HLA-B*4001 as a protective marker in Chinese population for showing bullous lesions (OR=0.14; 95% CI=0.06-0.32; P=3.2×10; I=0%). In summary, our meta-analysis showed the presence of HLA alleles contributing toward risk of as well as protection against various CBZ-induced cADRs.
    Pharmacogenetics and Genomics 12/2013; 24(2). DOI:10.1097/FPC.0000000000000021 · 3.45 Impact Factor


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