Phenytoin&HLA-B*1502



Scientific Studies & Publication
Phenytoin & HLA-B*1502
2011 \| 2010 \| 2009 \| 2008 \| 2007

2011
Title 1 : Biomarkers for antiepileptic drug response Biomark Med. 2011 Oct;5(5):635-41 Glauser TA The identification and validation of genetic factors ('biomarkers') that reliably predict the efficacy and toxicity of specific pharmacological agents for individual patients would significantly improve the current treatment of patients with epilepsy. A pharmacogenetic biomarker classification has been proposed that identifies three biomarker types involved in drug response: 'known valid biomarkers', 'probable valid biomarkers' and 'exploratory or research biomarkers'. The only known valid antiepileptic drug biomarker is HLA-B*1502 (Stevens-Johnson syndrome in patients of specific Asian backgrounds taking carbamazepine). Probable valid antiepileptic drug biomarkers include polymorphisms in one drug transporter gene, two drug metabolizing genes, three sodium channel genes and one HLA allele. Current methodological challenges to identifying new antiepileptic medication biomarkers can only be overcome with large-scale collaborative research efforts.


*Title 2 : Phenytoin-induced Stevens-Johnson syndrome with negative HLA-B1502 allele in mainland China: two cases.** Seizure. 2011 Jun;20(5):431-2. Epub 2011 Feb 18. Hu FY, Wu XT, An DM, Yan B, Stefan H, Zhou D Antiepileptic drugs-induced Stevens-Johnson syndrome (SJS) is a life-threatening severe cutaneous adverse reaction. Recent studies in Thailand and Taiwan showed a significant association between phenytoin (PHT)-induced SJS and human leucocyte antigen HLA-B1502 allele. Although the US FDA had issued an alert to clinicians, insufficient information is available to recommend testing for HLA-B1502 in Asian patients in line for PHT treatment. Therefore, extended studies are necessary to further evaluate the potential association between PHT-induced SJS and HLA-B1502 allele in various populations. To date, no similar data exist in mainland China. Here, we describe two Chinese Han cases of PHT-induced SJS with negative HLA-B1502 allele, in which HLA high-resolution genotyping showed two heterozygous HLA-B4601/B5102 and HLA-B3701/B4601 allele, respectively. Our findings provide evidence to support that other genetic markers or nongenetic factors could contribute to the susceptibility of PHT-induced SJS, except for HLA-B*1502 allele. Further studies are encouraged to investigate the genetic link with PHT-induced serious skin reactions in future.


*Title 3 : HLA-B1502 genotyping in two Chinese patients with phenytoin-induced Stevens-Johnson syndrome** Epilepsy Behav. 2011 Feb;20(2):390-1. Epub 2011 Jan 7 Min FL, Shi YW, Liu XR, Liao WP Previous studies have reported that patients with phenytoin-induced Stevens-Johnson syndrome and toxic epidermal necrolysis (PHT-induced SJS/TEN) were positive for HLA-B1502. We genotyped two patients with PHT-induced SJS using both polymerase chain reaction with sequence-specific primers and sequencing. The results revealed that one patient from Henan Province had HLA-B1501/B5401, and the other patient from Guangdong Province had HLA-B1502/B4601. When this information was combined with the results from Taiwan and Hong Kong, a significant difference was observed in the presence of HLA-B1502 between PHT-SJS and PHT-tolerant populations (35% vs 8%, P=0.001, OR=6.08, 95% CI=2.183-16.946). Additional studies in large samples are required to confirm the association between HLA-B*1502 and PHT-induced SJS/TEN.


*Title 4 : Should phenytoin and carbamazepine be avoided in Asian populations with the HLA-B1502 positive genetic variant?** Arch Dis Child. 2011 Jan;96(1):104-6. Ganesan S, Hussain N There is insufficient evidence to support routine HLA typing of all Asian patients prior to the commencement of antiepileptic drugs (AEDs). In Han Chinese, Malay and Thai patients, it is necessary to carry out HLA typing here feasible due to the higher risk of an adverse cutaneous drug reaction or use an alternative AED. Further clinical studies are needed for patients of Asian and non-Asian origin to determine the prevalence of the allele and the risk of Steven–Johnson syndrome/toxic epidermal necrolysis in patients on AEDs who test positive for HLA-B*1502.


2010
Title 1 : Common risk allele in aromatic antiepileptic-drug induced Stevens-Johnson syndrome and toxic epidermal necrolysis in Han Chinese Pharmacogenomics. 2010 Mar;11(3):349-56 Hung SI, Chung WH, Liu ZS, Chen CH, Hsih MS, Hui RC, Chu CY, Chen YT. Aims: Compared with other categories of drugs, such as antibiotics and NSAIDs, antiepileptic therapies are associated with a high incidence of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). We previously reported that carbamazepine (CBZ)-SJS/TEN is strongly associated with the HLA-B*1502 in Han Chinese, which has been confirmed in other Southeast Asian countries where the allele is prevalent. Here, we extend the study of HLA susceptibility to three different antiepileptic drugs, phenytoin (PHT), lamotrigine (LTG) and oxcarbazepine (OXC), which have structure similarity to CBZ.
Methods: We carried out a case-control association study. We enrolled 26 PHT-, six LTG- and three OXC-induced SJS/TEN patients, 113 PHT-tolerant and 67 LTG-tolerant subjects who were on the drug, respectively, for more than 3 months without the adverse reactions, and 93 normal subjects from the general population. The HLA-A, B, C and DRB1 genotypes were determined.
Results: We found that HLA-B1502 was present in eight out of 26 (30.8%) PHT-SJS/TEN (OR: 5.1; 95% CI: 1.8-15.1; p = 0.0041), two out of six (33%) LTG-SJS (odds ratio [OR]: 5.1; 95% CI: 0.8-33.8; p = 0.1266) and three out of three (100%) OXC-SJS (OR: 80.7; 95% CI: 3.8-1714.4; p = 8.4 x 10(-4)) patients. In addition, HLA-B1301, Cw0801 and DRB11602 also showed an association with PHT-SJS/TEN (p = 0.0128-0.0281; OR: 3.0-4.3).
Conclusion: Our results indicate that OXC, PHT and LTG, which possess an aromatic ring just as CBZ does, when causing SJS/TEN, share a common risk allele. Aromatic antiepileptic drugs causing SJS/TEN in HLA-B1502 carriers may act on a similar pathogenetic mechanism, although other genetic/nongenetic factor(s) may also contribute to the pathomechanism of the disease. We suggest that aromatic antiepileptic drugs, including CBZ, OXC and PHT, should be avoided in the B1502 carrier and caution should also be exercised for LTG.


2009
Title 1 : Genetic basis for idiosyncratic reactions to antiepileptic drugs Curr Opin Neurol. 2009 Apr;22(2):144-9 Franciotta D, Kwan P, Perucca E Purpose of review: In recent years, there has been an explosion of genetic research in epilepsy, including a search for genetic markers of adverse reactions to antiepileptic drugs. This article will focus on recent findings concerning genetic factors affecting susceptibility to idiosyncratic reactions to antiepileptic drugs.
Recent findings: Recent studies have investigated the role of genetic factors in the development of antiepileptic drug-induced cutaneous reactions, carbamazepine and valproate-induced liver toxicity, vigabatrin-induced visual field defects, and antiepileptic drug-induced teratogenicity. The greatest progress has been an improved definition of the role of human leukocyte antigen-related genes as predictors of the risk of serious antiepileptic drug-induced cutaneous reactions. This has led to the recommendation that patients of Asian ancestry be tested for the HLA-B*1502 allele, in order to identify those at high risk of developing Stevens-Johnson syndrome and toxic epidermal necrolysis after administration of carbamazepine and, possibly, phenytoin and other antiepileptic drugs.
Summary: Future research will probably lead to discovery of additional genetic predictors of susceptibility to adverse reactions to antiepileptic drugs. Identification of genetic markers should, in turn, allow unravelling of the molecular mechanisms underlying these reactions. Ultimately, these advances should lead not only to improved personalization of therapy but also to development of safer drugs.


2008
*Title 1 : Carbamazepine and phenytoin induced Stevens-Johnson syndrome is associated with HLA-B1502 allele in Thai population Epilepsia. 2008 Dec;49(12):2087-91. Epub 2008 Jul 14 Locharernkul C, Loplumlert J, Limotai C, Korkij W, Desudchit T, Tongkobpetch S, Kangwanshiratada O, Hirankarn N, Suphapeetiporn K, Shotelersuk V Purpose:** Previous studies found a strong association between HLA-B1502 and carbamazepine (CBZ)-induced Stevens-Johnson syndrome (SJS) in Han Chinese, but not in Caucasian populations. Even in Han Chinese, the HLA-B1502 was not associated with CBZ-induced maculopapular eruptions (MPE). This study seeks to identify whether HLA-B*1502 is associated with CBZ- or phenytoin (PHT)-induced SJS or MPE in a Thai population.
Methods: Eighty-one Thai epileptic patients between 1994 and 2007 from the Chulalongkorn Comprehensive Epilepsy Program were recruited. Thirty-one subjects had antiepileptic drug (AED)-induced SJS or MPE (6 CBZ-SJS, 4 PHT-SJS, 9 CBZ-MPE, 12 PHT-MPE), and 50 were AED-tolerant controls.
Results: For the first time, a strong association between HLA-B1502 and PHT-induced SJS was found (p = 0.005). A strong association was also found between the HLA-B1502 and CBZ-induced SJS (p = 0.0005), making Thai the first non-Chinese population demonstrating such an association. Some patients, who were HLA-B1502 and suffered from CBZ-induced SJS, could be tolerant to PHT and vice versa. This suggests that HLA-B1502 may be a common attribute required for a Thai patient to develop SJS from these two AEDs; other different elements, however, are also needed for each AED. In addition, no association between HLA-B alleles and CBZ- or PHT-induced MPE was found.
Conclusion: CBZ- and PHT-induced SJS, but not MPE, is associated with HLA-B*1502 allele in Thai population.


2007
*Title 1 : Association between HLA-B1502 allele and antiepileptic drug-induced cutaneous reactions in Han Chinese** Epilepsia. 2007 May;48(5):1015-8 Man CB, Kwan P, Baum L, Yu E, Lau KM, Cheng AS, Ng MH A previous study conducted in Taiwan found a 100% association between HLA-B1502 allele and carbamazepine-induced Stevens-Johnson syndrome (SJS) in Han Chinese subjects, with an extremely high odds ratio compared with carbamazepine-tolerant subjects (odds ratio = 2,504). We examined this association in 24 Hong Kong Han Chinese subjects who had cutaneous adverse reactions induced by different antiepileptic drugs (AEDs). They were matched with 48 AED-tolerant controls. HLA-B1502 was associated with severe cutaneous reactions (SCR) induced by AEDs, which included carbamazepine, phenytoin, and lamotrigine (p = 0.001, odds ratio = 17.6), but was not associated with maculopapular exanthema (MPE) (p = 0.32). Further studies in larger samples of ethnically matched subjects should be conducted to confirm the findings. Identification of genetic polymorphisms predisposing to development of AED-induced SCR offers the possibility of avoiding these high-risk drugs in genetically susceptible individuals.